JPH0469153B2 - - Google Patents

Abstract

It has been found that the novel compounds of the formula <CHEM> wherein R<1> is hydrogen or lower alkyl, R<2> is hydrogen or halogen, R<3> is hydrogen or lower alkyl, R<4> is hydrogen or lower alkyl, R<5> is hydrogen, lower alkyl or aralkyl, X is alkylene and n is an integer from 1 to 6, the enantiomers thereof and, when R<5> is hydrogen, the salts thereof with pharmaceutically acceptable bases have antiallergic properties and can accordingly be used as medicaments for the treatment or prevention of allergic conditions. The compounds of formula I can be manufactured by reacting a compound of the formula <CHEM> with a compound of the formula <CHEM> and optionally hydrolyzing the compound thus obtained.

Description

[Detailed description of the invention]

The present invention is based on the general formula In the formula, R ¹ is hydrogen or lower alkyl,
R ² is hydrogen or halogen, R ³ , R ⁴ and R ⁵
are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, R ⁶ and R ⁷ are both hydrogen, and R ⁸ is the group −COOR ⁹ ,
or R ⁶ is hydrogen or lower alkyl and R ⁷
is the group -( _CH2 )n- ^COOR9 , and ^R8 is hydrogen and ^R9 is hydrogen or lower alkyl,
X is ( _C3-7 )-alkylene and n is 0
is an integer of ˜4 and, when R ⁹ is hydrogen, its salts with pharmaceutically acceptable bases. These compounds are useful as agents for the treatment of allergic conditions. Objects of the present invention are the above-mentioned compounds and salts as such and as therapeutic agents; processes for the preparation of said products and intermediates for their manufacture; pharmaceutical compositions comprising said products and said pharmaceutical preparations. and the use of said products in the treatment or prevention of diseases. As used herein, the term "lower alkyl" refers to a straight or branched saturated hydrocarbon group containing up to 7, preferably up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
Butyl, t-butyl, neopentyl, pentyl,
Represents heptyl etc. The term "halogen" refers to bromine, chlorine, fluorine and iodine. "Ashiru"
The term represents lower alkanoyl groups derived from aliphatic carboxylic acids of up to 7 carbon atoms, such as formyl, acetyl, propionyl, etc.; and arylcarbonyl groups derived from aromatic carboxylic acids, such as benzoyl. The term "acyl" preferably represents a lower alkanoyl group. The term "( _C3-7 )-alkylene" refers to a straight-chain or branched group of 3 to 7 carbon atoms, such as propylene, 2-methylpropylene, butylene, pentamethylene, hexamethylene, heptamethylene, etc. . The term "aryl" refers to phenyl or phenyl having one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, and di-lower alkylamino. represents. The term "arylalkyl" refers to a straight or branched chain lower alkyl group in which one or more of the hydrogen atoms has been replaced with aryl, such as benzyl. Groups and compounds designated as lower contain up to 7, preferably up to 4 carbon atoms. Preferred compounds of the formula are of the general formula In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , X and n are as described above. Another preferred group of compounds of the invention is of the general formula In the formula, R ¹¹ is lower alkyl, R ³¹ is acyl, X is (C _3-7 )-alkylene, and n is an integer from 0 to 4. A further preferred group of compounds of the invention is in which R ¹ is lower alkyl, R ² is hydrogen, R ³ is acyl, R ⁴ , R ⁵ , R ⁶ and R ⁹ are hydrogen, and is ( _C3-5 )-alkylene. An even more preferred group of compounds of the invention is R ¹
is propyl, R ² is hydrogen, R ³ is acetyl, R ⁴ , R ⁵ , R ⁶ and R ⁹ are hydrogen,
and a compound of formula a, where X is ( _C3-5 )-alkylene. A preferred compound of the formula is: (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro- 2H−
1benzopyran-2-carboxylic acid, (S)-(+)-6-acetyl-7-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid, (racemic)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran- 2-Carboxylic acid, (racemic)-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-methyl-8-propyl-
2H-1-benzopyran-2-propanoic acid, (racemic)-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H -1-
Benzopyran-2-carboxylic acid, (racemic)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1
-benzopyran-2-carboxylic acid and (racemic)-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-benzopyran- 2-carboxylic acid. An example of a compound of formula is: (R)-(-)-6-acetyl-7-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid, (racemic)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran- 2-Butanoic acid, (racemic)-8-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]3,4-dihydro-7-acetyl-2H-1
-Benzopyran-2-carboxylic acid, (racemic)-5-acetyl-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-
1-Benzopyran-2-propanoic acid, (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-
1-benzopyran-2-butanoic acid and (racemic)-6-propanoyl-7-[7-(4
-acetyl-3-hydroxy-2-propylphenoxy)heptyloxy]-3,4-dihydro-
8-Propyl-2H-1-benzopyran-2-butanoic acid. In accordance with the present invention, compounds of the formula and pharmaceutically acceptable salts thereof are: (a) of the general formula or where R ⁶¹ and R ⁷¹ are both hydrogen and R ⁸¹ is a group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is a group -
( _CH2 )n- ^COOR91 , and ^R81 is hydrogen, ^R91 is lower alkyl, and
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as described above, and each compound has the general formula as well as where R ⁶¹ and R ⁷¹ are both hydrogen and R ⁸¹ is a group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is a group -
( _CH2 )n- ^COOR91 , and ^R81 is hydrogen, ^R91 is lower alkyl, X is ( _C3-7 )-alkylene, Z is a halogen atom, and ^R1 , R ² , R ³ , R ⁴ , R ⁵ and n
is as described above, or (b) the general formula In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶¹ , R ⁷¹ and
R ⁸¹ is as described above, the ester group in the compound is hydrolyzed, and the resulting racemate is optionally resolved into optically active isomers, and/or the resulting R ⁹ is hydrogen. It can be prepared by a process consisting of converting a compound of formula into a pharmaceutically acceptable salt with a base. The reaction of a compound of the formula with a compound of the formula and the respective reaction of a compound of the formula with a compound of the formula to form a compound of the formula c is carried out by reacting the reaction mixture in an inert solvent such as acetone, methyl ethyl ketone, diethyl ketone, dimethyl formamide, etc. It can be carried out under anhydrous conditions in dimethylformamide at reflux temperature, preferably in the temperature range from about 70 to about 100<0>C, in the presence of an acid acceptor such as potassium carbonate. A preferred solvent is a mixture of acetone and dimethylformamide. The resulting compound of formula c can be recovered using conventional methods such as crystallization, chromatography, etc. The resulting compound of formula c can be converted to the corresponding free acid by hydrolysis, preferably with an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. and hydrating solvents such as methanol,
It is carried out in a mixture of ethanol, tetrahydrofuran, etc. at about room temperature to reflux temperature. The resulting compounds can be recovered using conventional methods such as crystallization, chromatography, etc. The compounds of the formula and used as starting materials are known compounds, or can be produced according to known methods. Compounds of formula and used as starting materials can be prepared according to the following reaction scheme: In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹¹ , X, Z and n
is as above. In the reaction scheme, the formation of a compound of formula ' by the reaction of a compound of formula ', which is a known compound or can be prepared according to a known method, is performed using an inert organic solvent such as dimethylformamide, acetone, etc. , methyl ethyl ketone, etc., preferably in dimethylformamide, in the presence of a base such as an alkali metal carbonate, such as potassium carbonate, sodium carbonate, etc., or an alkali metal hydride, such as sodium hydride, at a temperature of from about 20°C to about
It can be carried out in a temperature range of 150°C, preferably at room temperature. The resulting compound of formula ' can be recovered using conventional methods such as crystallization, extraction, chromatography, etc. In the formula, R ⁶ , R ⁹¹ and n are as above,
R ³² , R ⁴² and R ⁵² are hydrogen or lower alkyl, and R is lower alkyl or aryl. In the reaction scheme, a compound of formula 'a is reacted with a base such as an alkali metal carbonate such as potassium carbonate, sodium carbonate, etc., or sodium hydride in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone, etc., preferably dimethylformamide. can be reacted with allyl halide in the presence of an alkali metal hydride, such as, at a temperature range of about 20 DEG C. to about 150 DEG C., preferably at room temperature, to form a compound of formula. The resulting compound of formula can be purified by conventional methods, e.g. crystallization,
It can be recovered using extraction, chromatography, etc. A compound of formula is converted to a compound of formula using conventional methods for hydroboration of olefins. For example, the formula (Q)
₂ BH, where Q is hydrogen, lower alkyl or lower cycloalkyl, using a hydride, preferably borane (BH ₃ ), dicyclohexylborane or borane-dimethylsulfide complex, in an inert ether solvent, preferably This conversion is carried out in tetrahydrofuran at a temperature range of about 0°C to about 100°C, preferably at room temperature. The resulting organoborane intermediate is oxidized, preferably using alkaline hydrogen peroxide, or the like. The resulting compound of formula can be recovered using conventional methods. A compound of the formula can be converted into a sulfonyl chloride of the formula RSO ₂ Cl, where R is alkyl or aryl, such as phenyl, using conditions advantageously used in converting alcohols to sulfonate esters, preferably methanesulfonate esters. to form a compound of formula a.
For example, sulfonation is carried out using a sulfonating agent, such as an alkylsulfonyl chloride, preferably methanesulfonyl chloride, in an inert solvent such as dichloromethane in the presence of a base such as a tri-lower alkylamine, pyridine, etc., preferably triethylamine, in the presence of a It is carried out at a temperature range of 0.degree. C. to about 25.degree. C., preferably 0.degree. The resulting compound of formula a can be recovered using conventional methods. Compounds of formula a are converted to compounds of formula 'a using conditions commonly used in converting sulfonate esters to iodides. For example, a compound of formula a is dissolved in a solvent such as a dialkyl ketone such as ethyl methyl ketone, acetone, etc., preferably acetone, at a temperature range of about 20°C to about 100°C, preferably 20°C, with an alkali metal iodide, e.g. Treat with sodium, lithium iodide, potassium iodide, etc., preferably sodium iodide.
The resulting compound of formula 'a can be recovered using conventional methods. Compounds of formula can also be converted to compounds of formula 'a by hydroboration and iodination under conditions commonly used in converting terminal olefins to primary iodides. For example, the reaction can be carried out using iodine and a hydride of the formula (Q) ₂ BH, where Q is hydrogen, lower alkyl or lower cycloalkyl, preferably cyclohexylborane, an inert ether solvent such as tetrahydrofuran and a base such as an alkali metal In the presence of a carboxylate salt, preferably sodium acetate, about 0
It can be carried out at a temperature range of 0.degree. C. to about 20.degree. The resulting compound of formula 'a can be recovered using conventional methods. In the formula, R ³² , R ⁴² , R ⁵² , R ⁶ and R ⁹¹ are as described above, and R' is arylalkyl, or in the reaction scheme, is a compound known as the compound of formula a, or _{The formation} ^of _compounds ^of _formula in an inert aromatic hydrocarbon solvent, preferably toluene, at about 20°C
It can be carried out at a temperature range from about 150°C, preferably about 110°C. The resulting compound of formula XI can be recovered using conventional methods. Compounds of formula XI can be converted to compounds of formula 'b by known methods for catalytic hydrogenolysis. For example, by treatment with hydrogen in a solvent such as an alkanol such as ethanol, preferably at room temperature and under 1 atmosphere of pressure, in the presence of a catalyst such as palladium on carbon. The resulting compound of formula 'b can be recovered using conventional methods. In the formula, R ³² , R ⁴² , R ⁵² and R ⁹¹ are as described above. In the reaction scheme, a compound of formula XII, which is a known compound or can be prepared according to known methods, is hydrogenated to form a compound of formula 'c.
More particularly, the reaction is carried out using a catalyst, e.g. This is done with palladium. The resulting formula 'c can be recovered using conventional methods. where R ³² , R ⁴² , R ⁵² , R ⁶ and R ⁹¹ are as described above, and n' is 2, 3 or 4. In the reaction scheme, a compound of formula which is a known compound or can be prepared according to known methods is combined in the presence of a catalyst such as a cyclic secondary amine, such as pyrrolidine, and an inert aromatic hydrocarbon, preferably toluene. The compounds of the formula below can be reacted with compounds of the formula that are known or can be prepared according to known methods at a temperature range of about 25°C to about 150°C, preferably 110°C. The resulting compound of formula can be recovered using conventional methods. A compound of the formula is prepared using borane in the presence of a Lewis acid such as boron trifluoride, boron trichloride, aluminum trichloride, etc., preferably boron trifluoride etherate, and an inert ether solvent such as tetrahydrofuran. , to a compound of formula'd at a temperature range of about 0°C to about 25°C, preferably 0°C. The resulting compound of formula 'd can be recovered using conventional methods. where R ⁴² , R ⁶ , R ⁹¹ and n are as described above and R'' is hydrogen or lower alkyl. In the reaction scheme, the phenolic compound of formula 'e is combined with a suitable acylating agent, e.g. using a lower alkanoyl halide or anhydride, preferably acetic anhydride, in a suitable base such as pyridine, lower alkyl amine, etc., preferably pyridine, at about 0°C.
to about 150°C, preferably 25°C, to the acyl derivative of formula. The resulting compound of formula can be recovered, if desired, using conventional methods. Compounds of formula can be converted to compounds of formula 'f using reaction conditions customary in carrying out the Fries rearrangement of phenyl acylates.
This conversion is carried out in the presence of a Lewis acid catalyst such as aluminum chloride, stannic chloride, boron trifluoride, etc., preferably a boron trifluoride etherate, and a solvent such as a halogenated hydrocarbon, a lower alkanoic acid, etc., preferably acetic acid. Inside, about 20℃~approx.
It can be carried out at a temperature range of 150°C, preferably 120°C. The resulting compound of formula 'f can be recovered using conventional methods. Compounds of formula 'e can also be converted to compounds of formula 'f under conditions common in performing Friedel-Crafts acylations of phenols. For example, the acylation can be carried out using a Lewis acid catalyst such as aluminum chloride, stannic chloride, boron trifluoride, etc., preferably aqueous boron trifluoride, and an acylating agent such as lower alkanoyl halides, lower alkanoyl anhydrides, lower alkanoic acids, etc. etc., preferably using acetic acid, from about 20°C to about
It can be carried out at a temperature range of 150°C, preferably 80°C. The resulting compound of formula 'f can be recovered using conventional methods. In the formula, R ³² , R ⁴² and R ⁵² are as above,
R is hydrogen or aryl-lower alkyl, preferably benzyl, and R ¹² is lower alkyl. In the reaction scheme, a compound of the formula etc., preferably using concentrated sulfuric acid, in a solvent such as a lower alkanol such as ethanol, methanol, etc., preferably methanol, at a temperature range of about 20°C to about 200°C, preferably
Treatment with acrolein at 150°C can produce compounds of formula XII. The resulting compound of formula XII can be recovered using conventional methods. The compound of formula
Preferably using dilute hydrochloric acid, in a water-miscible organic solvent such as acetone, methanol, ethanol, tetrahydrofuran, acetic acid, etc., preferably in acetone, at a temperature range of about 20°C to about 150°C, preferably 60°C. It is converted into a compound of In the reaction formula, R ³² , R ⁴² , R ⁵² , R ⁹¹ and R′ are as described above. Active organic ether solvents or aromatic hydrocarbons such as tetrahydrofuran, dioxane,
glyme, benzene, toluene, xylene, etc., preferably in toluene at a temperature range of about 20°C to about 200°C, preferably 110°C, are known compounds or can be prepared according to known methods. can be reacted with a compound to produce a compound of formula. The resulting compound of formula can be recovered using conventional methods. Compounds of the formula are reacted using conventional catalysts for hydrogenation such as palladium on carbon, platinum oxide, nickel, etc., preferably platinum oxide, in solvents such as lower alkanoic acids, ethyl acetate, etc.
about 20°C, preferably in the presence of ethyl acetate
Hydrogenation can be performed at a temperature range of from about 100<0>C, preferably at 20[deg.]C and atmospheric pressure, to form compounds of formula. The resulting compound of formula can be recovered using conventional methods. Compounds of formula V can be converted to compounds of formula V by saponification followed by lactonization. This saponification is carried out using an alkali metal hydroxide, preferably potassium hydroxide, in a solvent such as a lower alcohol, preferably methanol, from about 20°C to
It can be carried out at a temperature range of about 100°C, preferably 65°C. Lactonization can be carried out, for example, with a lower alkanoic anhydride, such as acetic anhydride, which can also be used as a solvent, at a temperature range from about 20 DEG C. to about 200 DEG C., preferably at the boiling point of the acetic anhydride. The resulting compound of formula can be recovered using conventional methods. A compound of formula is reacted using a common reducing agent such as di-lower alkylaluminum hydride, preferably diisobutylaluminum hydride, in an inert solvent such as an aromatic hydrocarbon, a chlorinated alkane or lower alkane, preferably dichloromethane. in a temperature range of about -50°C to about -100°C, preferably -75°C to the compound of formula b. The resulting compound of formula b can be recovered using conventional methods. In the formula, R ³ , R ⁴ , R ⁵ , R ⁹¹ , and X and Z are as described above. In the reaction scheme, the reaction of a compound of formula with a compound of formula ``to form a compound of formula '' is carried out using a base such as an alkali metal carbonate in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone, etc., preferably dimethylformamide. For example, it is carried out in the presence of potassium carbonate, sodium carbonate, etc., or an alkali metal hydride, such as sodium hydride, at a temperature range of about 20°C to about 150°C, preferably at room temperature. The resulting compounds of formula can be recovered using conventional methods such as crystallization, extraction, chromatography, etc. In the formula, R ³² , R ⁴² , R ⁵² , R ⁹¹ and R′ are as described above. In the reaction scheme, a compound of formula can be reacted with acrylonitrile to produce a compound of formula. This reaction is preferably carried out in the presence of a catalyst such as an amine such as triethylamine, diazabicycloundecene, preferably diazabicyclo(2.2.2)octane from about 20°C to about
It is carried out without solvent in a temperature range of 100°C, preferably 80°C. The resulting compound of formula can be recovered using conventional methods. A compound of the formula is dissolved in a solvent such as a water-miscible organic solvent such as tetrahydrofuran, methanol, ethanol, etc., preferably ethanol or tetrahydrofuran, at a temperature in the range of about 20°C to about 100°C, preferably 60°C to 70°C. For example, it can be converted to a compound of formula by saponification with an alkali metal hydroxide such as potassium hydroxide.
The resulting compound of formula can be recovered using conventional methods. The conversion of a compound of formula to a compound of formula is carried out using a lower alkanol such as ethanol as reagent and solvent and a catalyst such as a strong acid such as sulfuric acid, p-toluenesulfonic acid, etc., preferably p-
In the presence of toluenesulfonic acid, about 20℃ to approx.
This can be carried out by saponification at a temperature range of 100°C, preferably 78°C. The resulting compound of formula can be recovered using conventional methods. A compound of the formula is prepared using, for example, palladium, nickel, or platinum on a carrier, preferably palladium on carbon, in the presence of a solvent such as a lower alkanol, acetic acid, ethyl acetate, etc., preferably ethanol, at about 20 to 200°C. can be converted to the compound of formula "a" by catalytic hydrogenation in the temperature range of 20 DEG C. and under 1 atm, preferably 20 DEG C. and 1 atm.
The resulting compound of formula "a" can be recovered using conventional methods. where R ⁴² , R ⁹¹ and R'' are as described above. In Scheme XI, a compound of formula 'b is converted as described in Scheme XI for the conversion of formula 'e to 'f'. , directly or via compound XII, to a compound of formula 'c. where R ⁴² , R ⁶ , R ⁹¹ and R' are as described above and Z is halogen. In Reaction Scheme The reaction is carried out in the presence of an acceptor, such as potassium carbonate, at the reflux temperature of the reaction mixture, preferably in the range of about 40°C to about 100°C.
A preferred solvent is acetone. The resulting compounds of formula can be recovered using conventional methods such as crystallization, chromatography, etc. A compound of formula is prepared using a common reducing agent such as a di-lower alkyl hydride, preferably diisobutylaluminum hydride, in an inert solvent such as an aromatic hydrocarbon, chlorinated alkane, or lower alkane, preferably toluene. approx. -50℃
It can be converted to a compound of formula at a temperature range of from about -100°C, preferably -75°C. The resulting compound of formula can be recovered using conventional methods. where m is 0 or 1, and R ⁴² ,
R ⁶ , R ⁹¹ and R′ are as described above. In the reaction formula, the compound of the formula and the formula (C ₆ H ₅ ) ₃ P=CH(CH=CH) _n CO ₂ R ⁹¹ which is a known compound or can be produced according to a known method,
wherein R ⁹¹ is lower alkyl, preferably ethyl, and m is 0 or 1 to form a compound of the formula in an inert aromatic hydrocarbon solvent, preferably toluene. Temperature range from 20℃ to about 150℃, preferably about 110℃
It will be held in The resulting compound of formula can be recovered using conventional methods. Compounds of formula 'h can be converted to compounds of formula 'h' by known methods for catalytic hydrogenation of compounds of formula. Treatment with hydrogen, preferably at room temperature and 1 atmosphere, in a solvent such as an alkanol, such as ethanol or ethyl acetate, in the presence of a catalyst such as radium supported on carbon. The resulting compound of formula 'h can be recovered using conventional methods. The present invention also relates to pharmaceutically acceptable salts of compounds of formula wherein R ⁹ is hydrogen. The salts can be prepared by reacting the acid of formula with a base having a non-toxic pharmacologically and pharmaceutically acceptable cation. In general, bases that form salts with carboxylic acids and whose pharmacological properties do not result in adverse physiological effects when ingested by warm-blooded animals are intended to be within the scope of this invention. Thus, suitable bases include, for example, alkali metal and alkaline earth metal hydroxides or carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, etc.
Included are ammonia, primary, secondary, and tertiary amines such as monoalkylamines, dialkylamines, trialkylamines, nitrogen-containing heterocyclic amines such as piveridine, basic amino acids such as lysine, and the like. The pharmaceutically acceptable salts thus produced are functionally equivalent to the corresponding acids of the formula, and it is clear to one skilled in the art that the salts of the invention are therapeutically useful, and the salts of the invention The variety of salts encompassed by is limited only by the criteria that the base used to form the salt is non-toxic and physiologically acceptable. The useful antiallergic activity of compounds of formula can be demonstrated in vitro and in warm-blooded animals using standard pharmacological methods. Examples of such methods are: (a) Guinea pig ileum test (in vitro): The guinea pig ileum bioassay system is
Adv. Immunol. 10 by Orange and Austen,
105-144 (1969). Weight 300~
A 1.5 cm segment was removed from a 400 g animal and suspended in an organ bath containing 10 ml of Tyrode's solution of 10 ^-6 M atropine sulfate and 10 ^-6 M pyrylamine maleate. The bath was maintained at 37°C and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. The SRS-A used in this screening was actively sensitized in vitro with ovalbumin.
sensitized) obtained by challenging lung fragments cut from guinea pigs. A dose-response curve for the SRS-A challenge was established for the ileum. The next dose of SRS-A that produces 50% of the maximal contraction (ED ₅₀ )
The following challenge was used. The concentration of drug that inhibits SRS-A-induced contractions of guinea pig ileum by 50% (IC ₅₀ ) was determined. In this bioassay system, standard SRS-A antagonist, 7-[3-(4-acetyl-3-
Hydroxy-2-propylphenoxy)-2-
Hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid has an IC ₅₀ of 3.5×10 ⁸ M. (b) Guinea pig bronchial constriction test (in vivo; aerosol): Male guinea pigs (Hartley species) weighing 300 to 500 g were anesthetized intraperitoneally with urethane (2 g/Kg), and the drug was administered. A polyethylene cannula was inserted into the jugular vein. Insert the tracheal pressure into the trachea and Statham pressure transducer
Recorded from the cannula connected to the After the animals were surgically treated, there was a period of time to allow lung function to stabilize. Test compounds were administered according to the following protocol. Propanol (0.1mg/
Kg) was administered intravenously. Five minutes later, the animals were exposed to a 1% (w/v) aerosol solution of the test compound (alkaline pH required to dissolve the drug).
(adjusted to PH value) or distilled water at the appropriate PH value (for control purposes) for 5 minutes. A Monaghan (Model 750) ultrasonic nebulizer was used to administer all test compounds by inhalation. The ultrasonic frequency of the nebulizer was adjusted to produce particles in the 1-8μ diameter range (average 3μ). The aqueous solution was freshly prepared and introduced into the nebulizer chamber. Biasing the aerosol through the Y-tube connected to the tracheal cannula
The outlet of the nebulizer was directed so that the flow was directly available to the animal. At the end of the exposed trachea, the animals were paralyzed with succinylcholine (1.2 mg/Kg, iv) and mechanically ventilated at 40 breaths/min and a respiratory volume of 2.5 cc (Harvrad rodent respirator). . Next, the animals
Thirty seconds after administration of succinylcholine, the maximal systolic dose of leukotriene E ₄ given intravenously was allowed to range. Changes between pre-treatment and peak ventilatory pressure readings (cmH ₂ O) were averaged for 3 control animals and 5 drug-treated animals. Percentage inhibition was calculated from the following formula: control animals - drug-treated animals/control animals x 100 When tested at various drug concentrations, the percentage inhibition at each concentration was calculated as the percentage inhibition (vertical axis) versus the log concentration (horizontal axis). ) and the IC ₅₀ was determined from linear regression analysis. When compounds of the formula shown in the following table were used in the above test method, the results shown in the table were obtained:

[Table] Acid

【table】

[Table] When replacing leukotriene E ₄ with leukotriene D ₄ in the above aerosol assay,
(racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
-1-Benzopyran-2-carboxylic acid was found to exhibit an _IC50 value of 0.0056% in inhibiting tracheal stenosis; (R)-(-)-6-acetyl-7-
[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4
-Dihydro-2H-1-benzopyran-2-carboxylic acid 0.0018% in inhibiting bronchial stenosis
It is found that it exhibits an IC ₅₀ value of; and (S)−
(+)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)
pentyloxy]-3,4-dihydro-2H-1
-Benzopyran-2-carboxylic acid was found to exhibit an IC ₅₀ value of 0.0018% in inhibiting tracheal stenosis. (c) Oral test of leukotriene antagonist Male guinea pigs (Hartley breed, Charles River) weighing 400-600 g were anesthetized intraperitoneally with urethane (2 g/Kg), and a polyethylene cannula was inserted into the jugular vein to administer the drug. inserted inside. Tracheal pressure (cmH ₂ O) was recorded from a Statham pressure transducer. After the animal was surgically prepared, there was a period of time to allow natural breathing to stabilize. Propanolol was administered 5 minutes before leukotriene challenge because previous studies demonstrated the synergistic effect of propanol (0.1 mg/Kg, iv) on bronchoconstriction induced by synthetic leukotrienes. 2 minutes later,
Natural breathing succinylcholine hydrochloride (1.2
The animal was restrained (mg/Kg, iv) and breathed with a Harvard (model #580) small animal ventilator at 40 breaths/min and a stroke volume of 4.0 cc. The animals were treated with leukotriene C ₄ , leukotriene D ₄ or leukotriene E ₄ (25 μg/
Kg, iv) for 5 minutes to challenge maximal systolic dosage. Two hours before the leukotriene challenge, the control formulation or test drug (adjusted to the PH value required for drug dissolution) was administered (10 mg/Kg, po). To determine the ID ₅₀ for the test drug, the dosage was 10 mg/Kg,
100, 50, 30, 20, 5, 3 and mg/Kg from po,
Changed to po. The time between test drug exposure and leukotriene challenge was varied to determine the oral duration of effect. In test method (c), among the compounds tested by this oral method, (racemic)-6-acetyl-7-[5-(4-acetyl-3 -Hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-
1-Benzopyran-2-pentanoic acid showed a 46±14% inhibition of leukotriene _D4- induced bronchial stenosis. Compositions comprising a therapeutically effective amount of a compound of formula, or a salt thereof when R ⁹ is hydrogen, or a salt thereof when R ⁹ is hydrogen, are well known in the art. It can be administered by known methods. Thus, the compounds according to the invention may be used alone or together with other agents such as antihistamines, mediator release inhibitors, methylxanthines, beta-agonists or antihistamine steroids such as brednisone and brednisolone. It can be administered orally, parenterally, rectally or by inhalation, for example in the form of an aerosol, micronized powder or spray solution. For oral administration, the compounds may be in the form of tablets, capsules, in combination with e.g. talc, starch, lactose or other inactive ingredients, i.e., pharmaceutically acceptable carriers, or in combination with e.g. They can be administered in the form of aqueous solutions, suspensions, elixirs or hydroalcoholic solutions in combination with sweeteners, flavors, colorants, thickeners and other common pharmaceutical excipients. For parenteral administration, the compounds can be administered as solutions or suspensions, eg, aqueous or peanut oil solutions or suspensions, using the usual excipients or carriers for this mode of administration.
For aerosol administration, the compound can be dissolved in a suitable pharmaceutically acceptable solvent such as ethyl alcohol or a combination of miscible solvents and mixed with a pharmaceutically acceptable propellant carrier. . Such aerosol compositions are used in pressure containers equipped with suitable aerosol valves for discharging the composition under pressure. Preferably, the aerosol valve is a metered valve, ie, a valve that releases a predetermined effective dosage of the aerosol composition. Currently, the most preferred route of administration for compounds of formula is inhalation, eg as an aerosol, especially for use as an anti-asthmatic agent. In practicing this invention, the dosage and frequency of administration of the compound of formula administered, or salt thereof when R ⁹ is hydrogen, will depend on the potency and duration of activity of the particular product administered and the route of administration. It will also depend on the severity of the symptoms, the age of the warm-blooded animal being treated, etc. The dosage of a compound of formula or a salt thereof contemplated for use in the practice of this invention is from about 25 to 1000
mg/day, preferably from about 25 to about 250 mg as a single or divided dose per day. Since the compounds of the formulas of the present invention have asymmetric carbon atoms, the compounds are usually obtained as racemic mixtures. Such resolution of the racemate into optically active isomers can be carried out by known methods. Certain racemic mixtures can be precipitated as eutectics;
And then it can be separated. However, chemical resolution is preferred. By this method, racemic mixtures of compounds of the formula in which R ⁹ is hydrogen can be reacted with an optically active resolving agent, e.g. an optically active base e.g. a carboxyl group, d-(+)-α
-Generation of diastereomers with methylbenzylamine. The resulting diastereomers are separated by fractional crystallization and converted into the corresponding optical isomers. Thus, the present invention encompasses racemic forms of compounds of formula as well as optically active isomers (enantiomers) thereof. This resolution can also be carried out using the corresponding acid of the ester of the formula as an optically active amine resolving agent such as (R)- or (S)-α-methylbenzylamine, (R)- or (S)-α-naphthylethylamine, quinine , quinidine, efuedrine, etc., preferably by treatment with (R)- or (S)-α-methylbenzylamine. After separation of the diastereomeric salts as described above, the optically active acids obtained are recovered by acid treatment and converted to the corresponding esters, as described for the preparation of the racemic system. Convert to the corresponding optically active compound. In addition, this resolution can be accomplished by treating the corresponding acid of the ester of formula or with an optically active alcohol to produce a mixture of diastereomeric esters that can be separated by crystallization or chromatography. ,It can be carried out. Typical optically active alcohol resolving agents are menthol,
These include borneol, 2-octanol, 2,3-butanediol, and the like. The preferred method of partitioning is
Included are monoesters of 2R,3R-butanediol and acids derived from esters of formula or. These esters can be produced using conventional methods. A preferred method is conventional Fisher esterification using a strong acid catalyst. A preferred acid catalyst is p-toluenesulfonic acid. Diastereomeric esters of acids of the formula can be produced by alkylation of the corresponding diastereomers of the formula with dihaloalkanes of the formula using conventional methods described above. The preferred chromatographic method for performing the resolution is high performance liquid chromatography (HPLC). After separation, the diastereomeric ester with the resolved acid of the formula is converted to the corresponding resolved acid of the formula using the conventional methods described above for racemates. In the following examples, all reactions were carried out under an inert atmosphere (argon). "Conventional processing" or "common method processing" includes three extractions with a particular solvent. The organic extracts are then combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under water pump vacuum. The residue is dried at 40-50° C./under high vacuum to constant weight. Column chromatography is performed using silica gel 0.063-0.2 mm. The following examples further illustrate the invention. All temperatures are in degrees Celsius unless otherwise noted. Example 1 30.4 g of 2',4'-dihydroxyacetophenone,
A mixture of 28.8 g of ethyl levulinate, 21.3 g of pyrrolidine and 400 ml of toluene was stirred and refluxed for 3 hours with water removed using a Dean-Stark trap.
The resulting mixture was cooled in an ice bath and added with 300 ml of 1.2N hydrochloric acid.
Processed with. After stirring at room temperature for 45 minutes, the mixture was treated with ether and the aqueous layer was separated. organic solution
Washed with 1.2N hydrochloric acid. The acidic aqueous solutions were combined and extracted twice with ether. Combine the organic solutions, add water,
washed with saturated aqueous sodium bicarbonate solution and brine;
It was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The remaining red oil (42 g) was chromatographed on 400 g of silica gel. 9:
32.3 g of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester as an orange viscous oil, eluted with 1 toluene-ethyl acetate.
(58.1%). Example 2 Racemic-3 in 8 ml of dry tetrahydrofuran,
4-dihydro-7-hydroxy-2-methyl-4
-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in a stirred solution of 1.5 g;
While cooling in an ice bath, 1.4 ml of boron trifluoride etherate was added over 2 minutes. The mixture was stirred for 5 minutes at 0-5°C, then 5.4ml of 1M borane in tetrahydrofuran was added. Stirring to 0
It lasted 2.5 hours at ˜5° C. and then the mixture was decomposed by the addition of glacial acetic acid. The solvent was removed under vacuum and the residue was then dissolved in methylene chloride. The solution was washed with sodium bicarbonate solution and brine, dried,
filtered and concentrated under reduced pressure. The remaining orange oil (1.4 g) was chromatographed on 50 g of silica gel. Elution with 4:1 hexane-ethyl acetate gave racemic 3,4-dihydro-7 as a colorless oil.
-Hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester 0.9g
(63.1%). Elemental analysis: Calculated _{for C15H20O4} : _C.68.16 ; H.7.63. Actual value: C.67.86; H.7.60. Example 3 In 0.5 ml of dry N,N-dimethylformamide
To a stirred slurry of 120 mg of 50% sodium hydride-mineral oil dispersion was added racemic 3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran- in 3 ml of dry N,N-dimethylformamide.
A solution of 292 mg of 2-propanoic acid ethyl ester was added. The mixture was stirred at room temperature for 25 minutes, at which point it was dissolved in 3 ml of dry N,N-dimethylformamide.
4'-(3-bromopropoxy)-2'-hydroxy-
A solution of 364 mg of 3'-n-propylacetophenone was added. After stirring for 21 hours at room temperature, the mixture was treated with ether and dilute hydrochloric acid and treated with ether in the usual manner to give 523 mg of an orange oil. This material was chromatographed on 50 g of silica gel.
Elution with 19:1 toluene-ethyl acetate yielded racemic 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy] as a pale yellow oil.
-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester 257
mg (46.5%). Elemental analysis: Calculated for _C29H38O7 : _C.69.86 ; _H.7.68 . Actual value: C.69.65; H.7.73. Example 4 To a mixture of 1.55 g of the ester according to Example 3 and 35 ml of 1:1 tetrahydrofuran-water was added, with stirring, 2.3 g of lithium hydroxide hydrate. The mixture was stirred at room temperature for 22 hours, then diluted with water and extracted three times with ether (the ether extract was discarded). The aqueous solution was made acidic to a pH value of 1 by addition of saturated aqueous oxalic acid solution and treated with ether in the usual manner. Racemic 7-[3] as a viscous yellow oil
1.4 g (95.8%) of -(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid was obtained. . Elemental analysis: Calculated _{for C27H34O7} : C.68.92; _H.7.28 . Actual value: C.69.62; H.7.23. Example 5 A mixture of 3.88 g of 2',4'-dihydroxy-3'-n-propylacetophenone, 3.17 g of levulinic acid, 0.83 ml of propyridine and 20 ml of toluene was prepared at room temperature.
The mixture was stirred for an hour and then refluxed for 3 hours with water removed using a Dean-Stark trap.
The resulting dark-brown mixture was cooled and diluted with 25 ml of 1N hydrochloric acid.
ml and stirred at room temperature for 30 minutes. Add water;
The mixture was treated with ether in the usual manner to give 5.1 g of a dark red oil. This material was chromatographed on 100 g of silica gel. 9:1 and 4:1
Elution with toluene-ethyl acetate gave racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-3-n-propyl-2H-1 as a yellow oil.
-Benzopyran-2-propanoic acid ethyl ester
2.9g (45.3%) was obtained. Elemental analysis: Calculated for _C18H24O5 : _C.67.48 ; _H.7.55 . Actual value: C.67.31; H.7.54. Example 6 Using the method of Example 2, racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-n-propyl-2H-1-benzopyran-
257 mg of 2-propanoic acid ethyl ester was added to borane-
Reduction was performed with tetrahydrofuran and boron trifluoride etherate. After chromatographic purification on silica gel, racemic 3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-
195 mg of 2-propanoic acid ethyl ester was obtained. Elemental analysis: Calculated _{for C18H26O4} : _C.70.56 ; H.8.55. Actual value: C.70.01; H.8.28. Example 7 50 in 1 ml of anhydrous N,N-dimethylformamide
To a stirred slurry of 108 mg of % sodium hydride-mineral oil dispersion (prewashed with hexane) was added racemic 3,4-dihydro-7-hydroxy-2-methyl-3- in 3 ml of dry N,N-dimethylformamide. n-propyl-2H-1-benzopyran-
A solution of 268 mg of 2-propanoic acid ethyl ester was added over 1 minute at room temperature. After stirring for 30 minutes at room temperature, the mixture was dissolved in 4'-(3-bromopropoxy)-2'- in 3 ml of dry N,N-dimethylformamide.
Hydroxy-3'-n-propylacetophenone
It was treated dropwise with 313 ml of solution. Sodium iodide (0.3 g) was added and the mixture was stirred at room temperature for 2.5 h.
Next, the reaction was stopped with 1 ml of water. After 30 minutes, add 0.3 g of lithium hydroxide hydrate and 1 ml of water, and continue stirring for 3
It lasted for hours. The mixture was acidified to a pH value of 1 with 1N hydrochloric acid and treated with ether in the usual manner. The orange oil (0.7 g) was chromatographed on 50 g of silica gel. Racemic 7-[3-(4-acetyl-3-
Hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-
310 ml (69.1%) of n-propyl-2H-1-benzopyran-2-propanoic acid was obtained. Elemental analysis: Calculated for C ₃₀ H ₄₀ O ₇ : C.70.29; H.7.87. Actual value: C.70.19; H.7.99. Example 8 Using the method of Example 1, 15 g of 2',5'-dihydroxyacetophenone was condensed with 14.2 g of ethyl levulinate and 12.3 ml of pyrrolidine in 200 ml of toluene. The crude product (20.5 g) was purified by high performance liquid chromatography (silica gel; 2:1 hexane-ethyl acetate) and the ceramide 3,4-dihydro-6-hydroxy-2-methyl- 4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester 17.6g
(64.1%). Elemental analysis: Calculated for _C15H18O5 : _C.64.74 ; _H.6.52 . Actual value: C.64.27; H.6.64. Example 9 Racemic 3,4-dihydro- in 50 ml of dry grime
6-hydroxy-2-methyl-4-oxo-2H
7.29 ml of boron trifluoride etherate was added dropwise to a solution of 8.2 g of -1-benzopyran-2-propanoic acid ethyl ester while stirring and cooling in an ice bath. Stirred for 10 minutes at 0-5°C. The mixture was treated with 1.75 g of borane-dimethylamine complex. Stirring was continued for 1 hour at room temperature, at which point 5 ml of glacial acetic acid were added and the solution was poured into cold water and treated with ether in the usual manner (the combined organic extracts were further washed with sodium bicarbonate solution). The crude product was found to contain a substantial amount of starting ketone;
It was again subjected to the reduction step and treatment described above. yellow oil
8.1 g was obtained, which was purified by preparative high performance liquid chromatography (silica gel,
2:1 hexane-ethyl acetate), yielding 5.8 g (74.1%) of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil. Example 10 Using the method of Example 7, racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-
Benzopyran-2-propanoic acid ethyl ester
0.695 g of alkyl 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone 0.939 g using sodium hydride and sodium iodide in dry N,N-dimethylformamide. It became. After saponification (1.25 g of lithium hydroxide hydrate), 1.4 g of crude acid was obtained. Column chromatography on silica gel (50 g) gave the racemic 6-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2 as a colorless oil. -Methyl-2H-1-benzopyran-2-propanoic acid
Obtained 0.837g (eluted with 9:1 and 4:1 toluene-ethyl acetate). Elemental analysis: Calculated _{for C27H34O7} : C.68.92; _H.7.28 . Actual value: C.68.36; H.7.20. Example 11 Using the method of Example 7, racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-
0.9 g of benzopyran-2-carboxylic acid was dissolved in 4'-(3-bromopropoxy)-2'- in N,N-dimethylformamide using sodium hydride (12.16 mmol) and sodium iodide (10 mmol).
Alkylation was performed with hydroxy-3'-n-propylacetophenone (1.5 g). After saponification with lithium hydroxide-hydrate (1.5 g), the crude acid product was purified by chromatography on silica gel. Racemic 6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy] as an off-white solid with a melting point of 108-110.5°C.
1.16 g (68.9%) of -3,4-dihydro-2-ethyl-2H-1-benzopyran-2-carboxylic acid was obtained. Elemental analysis: Calculated for _C25H30O7 : _C.67.86 ; _H.6.83 . Actual value: C.67.92; H.6.97. Example 12 365 mg of 50% sodium hydride dispersion in mineral oil was washed with hexane and suspended in 32 ml of anhydrous N,N-dimethylformamide. To this stirred slurry was added 1 g of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester. After stirring for 45 minutes at room temperature, the mixture was treated dropwise with 3.2 ml (4.47 g) of allyl bromide. Stirring was continued for 90 hours at room temperature, at which point 3 ml of methanol were added. The mixture was poured into water and treated with ether in the usual manner to give 1.8 g of an amber oil. This material was purified by column chromatography on silica gel followed by preparative high performance liquid chromatography (silica gel, 19:1 hexane-ethyl acetate). Racemic 3,4 as a pale yellow oil
-dihydro-2,5,7,8-tetramethyl-6
-(2-propenyloxy)-2H-1-benzopyran-2-carboxylic acid methyl ester 772mg
(67.2%) was obtained. This material was distilled evaporatively to give an oil with a boiling point of 105-107°C (bath temperature) (0.02 mm), which crystallized into a solid on standing.
Melting point 68-70℃. Elemental analysis: Calculated for _C18H24O4 : _C.71.03 ; _H.7.95 . Actual value: C.71.37; H.7.90. Example 13 Racemic 3,4 in 36 ml of anhydrous tetrahydrofuran
-dihydro-2,5,7,8-tetramethyl-6
To a solution of 1.8 g of -(2-propenyloxy)-2H-1-benzopyran-2-carboxylic acid methyl ester was added 1.98 ml of borane-dimethylsulfide while stirring and cooling in an ice bath. Reaction mixture to 0
Stirred for 1.5 hours at ˜5° C. then decomposed by addition of 9 ml of water. After stirring for 10 minutes at 0-5°C, the mixture was treated dropwise with 6.84 ml of 3N sodium hydroxide and then with 2.2 ml of 30% hydrogen peroxide. mix 5-10
The mixture was stirred for 1 hour at 0.degree. C. and then acidified with 7 ml of 3N hydrochloric acid. 2 g of oil was obtained by treatment with ether in a conventional manner, and this was subjected to preparative HPLC (silica gel,
Purified by 1:1 hexane-ethyl acetate). Racemic 3,4-dihydro- as a colorless oil
2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2
-1.22 g (64%) of carboxylic acid methyl ester were obtained. Elemental analysis: Calculated value for C ₁₈ H ₂₆ O ₅ : C, 67.06; H, 8.13 Actual value: C, 67.39; H, 8.19 Example 14 Anhydrous methylene chloride 5 ml and triethylamine
Racemic 3,4-dihydro-2,5, in 0.33ml
0.17 ml of methanesulfonyl chloride was added to a solution of 0.3 g of 7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester. The mixture was stirred at room temperature for 45 minutes, then treated with 1N sulfuric acid and methylene chloride in the usual manner. Racemic 3,4-dihydro-2,5,7,8-tetramethyl-6-(3-methanesulfonyloxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester was obtained as an oil; Used without further purification. Example 15 Crude methanesulfonate according to Example 14 (ca.
A mixture of 0.932 mmol), 595 mg of sodium iodide and 5 ml of acetone was stirred at room temperature for 43.5 hours, then treated with water and ether in the usual manner (the ether extract was further washed with dilute sodium bisulfite solution). . The oily product (390 mg) was chromatographed on 20 g of silica gel.
Racemic 3,4-dihydro-
306 mg (76.0%) of 2,5,7,8-tetramethyl-6-(3-iodopropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester was obtained.
In other experiments, iodide produced by this method became a crystalline solid, with a melting point of 73-75.5°C. Example 16 A mixture of 0.137 g of 2',4'-dihydroxy-3'-n-propylacetophenone, 0.195 g of anhydrous potassium carbonate, and 3 ml of anhydrous N,N-dimethylformamide was stirred at room temperature for 1 hour. A solution of iodide (0.306 g) according to Example 15 in 5 ml of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 30 min.
and stirred at 60° C. for 31 hours. After cooling, the reaction mixture was treated with 1N hydrochloric acid and ether in the usual manner. The oily product (0.406 g) was chromatographed on 20 g of silica gel.
Elution with 4:1 hexane-ethyl acetate yielded racemic 6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy] as a pale yellow oil.
0.291 g (82.5%) of -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was obtained. In other experiments, the material produced in this way crystallized to give a colorless solid, melting point 121-123 °C (crystallized from ethanol). Elemental analysis: Calculated for C ₂₉ H ₃₈ O ₇ : C, 69.86; H, 7.68 Found: C, 69.31; H, 7.67 Example 17 0.246 g of the methyl ester according to Example 16 in 8 ml of methanol and 2 ml of water and water sodium oxide
The 0.227 g solution was stirred at room temperature for 1.5 hours, then treated with 1N hydrochloric acid and ether in the usual manner.
The crude product was redissolved in ether and the solution was washed with dilute sodium bicarbonate solution. The alkaline aqueous phase was acidified with 2N hydrochloric acid and treated with ether in the usual manner to give 0.161 g (67.3%) of the acid as a yellow oil.
was obtained, which crystallized upon standing. Recrystallized from benzene-hexane, melting point 137-139℃
racemic 6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) as a colorless solid.
propoxy]-3,4-dihydro-2,5,7,
8-tetramethyl-2H-1-benzopyran-2
-carboxylic acid was obtained. Elemental analysis: Calculated for _C28H36O7 : C, 69.40; H, 7.49 Observed: C, 69.28; H, 7.58 Example 18 Using the method of Example 12, racemic 3,4 _- dihydro _- 2 , 1.42 g of 5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-acetic acid methyl ester were mixed with allyl bromide (2.79 g) and sodium hydride (5.58 g) in anhydrous N,N-dimethylformamide. mmol). After purification by column chromatography (silica gel, 9:1 hexane-ethyl acetate), racemic 3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)- was obtained as a yellow oil. 2H−
1-benzopyran-2-acetic acid methyl ester 1.35
g (83.1%) was obtained. Elemental analysis: _Calculated for _C19H26O4 : C, _71.67 ; H, 8.23 Found: C, 71.54; H, 8.25 Example 19 Dry in a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml). Tetrahydrofuran 6
A solution of 2 ml (1.64 g) of cyclohexene in ml was added dropwise. This mixture was stirred at 0-5°C for 1.5 hours. A solution of 1.59 g of the allyl ether according to Example 18 in 4 ml of tetrahydrofuran was added dropwise to the resulting slurry of dicyclohexylborane. The mixture was stirred for 1 hour at 0-5°C and 18 hours at room temperature, at which point 20 ml of 1M methanolic sodium acetate was added dropwise, followed by 23.8 ml of 0.4M methanolic iodine. The resulting mixture was stirred at room temperature for 4 hours, then 3.1 ml of aqueous sodium thiosulfate solution was added. The reaction mixture was poured into water and treated with ether in the usual manner. The crude product (4.4 g) was dissolved in silica gel 100
chromatographed on g, eluting with 19:1 and 9:1 hexane-ethyl acetate to give racemic 3,4-dihydro-6-(3-iodopropoxy)-2,5,7,8-tetra as an oil. Methyl-2H-
1-benzopyran-2-acetic acid methyl ester 1.71
g (76.7 g) was obtained. Example 20 Using the method of Example 16, 328 mg of 2',4'-dihydroxy-3'-n-propylacetophenoxy was prepared in Example 19 in anhydrous N,N-dimethylformamide.
with 756 mg of iodide and anhydrous potassium carbonate (467 mg). After column chromatography (silica gel, 4:1 hexane-ether), racemic 6-[3-(4
-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,
5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid methyl ester 0.789g (91.1%)
was gotten. Example 21 Using the method described in Example 17, a 0.669 g sample of the methyl ester according to Example 20 was saponified with sodium hydroxide. Silica gel crude acid product
Chromatographed on 30g. Elution with 2:1 hexane-ethyl acetate gave the racemic 6-[3-(4-acetyl-3-hydroxy-
2-propylphenoxy)propoxy]-3,4
-dihydro-2,5,7,8-tetramethyl-
2H-1-benzopyran-2-acetic acid 0.386g (59.6
%) was obtained. Elemental analysis: Calculated for _C29H38O7 : C, _69.86 ; H, 7.68 Found: C, 69.63; H, 7.89 Example 22 Racemic 3,4 _- dihydro-7 in 8 ml of pyridine
-Hydroxy-2-methyl-8-n-propyl-
Acetic anhydride was added to a stirred solution of 0.8 g of 2H-1-benzopyran-2-propanoic acid ethyl ester.
Added 0.37ml. The solution was stirred at room temperature for 5 hours, then poured into ice water and treated with ether in the usual manner (the combined ether extracts were further washed with 1N hydrochloric acid and saturated sodium bicarbonate solution). The oily product (1.0 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate yielded racemic 7-acetoxy-3,4-dihydro-2-methyl-8-n as a pale yellow oil.
-Propyl-2H-1-benzopyran-2-propanoic acid ethyl ester 0.575 g (63.3%) was obtained. Elemental analysis: Calculated for _C20H28O5 : C, 68.94; H, 8.10 Found: C, 68.73; H, 8.06 Example 23 Racemic 7 _- acetoxy _- 3,4 in 2 ml of glacial acetic acid
-dihydro-2-methyl-8-n-propyl-
To a stirred solution of 276 mg of 2H-1-benzopyran-2-propanoic acid ethyl ester was added 0.21 ml of boron trifluoride etherate at room temperature. The mixture was stirred at 105° C. for 24 hours, then cooled and diluted with ether. The ether solution was washed with water and brine and worked up in the usual manner to give 298 mg of a yellow-brown oil. This material was chromatographed on 30 g of silica gel. Racemic 6-acetyl-3,4-dihydro- eluted with 4:1 toluene-ethyl acetate as an off-white solid, mp 154-156°C.
7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid 183mg
(72.1%). Elemental analysis: Calculated for _C18H24O5 : C, _67.48 ; H, 7.55 Found: C, 67.17; H, 7.72 Example 24 Racemic 6 _- acetyl- in 10 ml of absolute ethanol
3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-
A solution of 692 mg of 2-propanoic acid and 100 ml of p-toluenesulfonic acid hydrate was stirred and refluxed for 17 hours. The resulting solution was cooled, treated with a small amount of saturated sodium bicarbonate solution, and then concentrated under vacuum to remove ethanol. The residue was treated with ether and the ether solution was treated in the usual manner to give a yellow oil.
Obtained 752 mg. This material was chromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethyl acetate yielded racemic 6-acetyl-3,4-dihydro-7-hydroxy-2- as a yellow oil.
Methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester 706mg
(93.9%). Elemental analysis: Calculated value for _C20H28O5 : C, _68.94 ; H, 8.10 Actual value: C, 68.86; H, 7.85 Example 25 Racemic 6 _- acetyl-3,4-dihydro-7-
Hydroxy-2-methyl-8-n-propyl-
2H-1-benzopyran-2-propanoic acid ethyl ester 263 mg, anhydrous potassium carbonate 222 mg, 1,3
- A mixture of 0.39 ml dibromopropane, 6 ml anhydrous acetone and 3 ml anhydrous N,N-dimethylformamide was stirred and refluxed for 16 hours. An additional 0.25 g of anhydrous potassium carbonate was added and stirring and refluxing continued for 25 hours. The mixture was cooled and the volatiles were removed first under water pump vacuum and then under high vacuum. The residue was treated with ether and acetone and the solids were removed by filtration. The filtrate was concentrated under vacuum to give racemic 6-acetyl-7-(3
-bromopropoxy)-3,4-dihydro-2-
359 mg of methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester was obtained. Example 26 Racemic 6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n
-Propyl-2H-1-benzopyran-2-propanoic acid ethyl ester 335 mg, 2',4'-dihydroxy-3'-n-propylacetophenone 143 mg,
A mixture of 217 mg of anhydrous potassium carbonate, 6 ml of anhydrous acetone and 3 ml of anhydrous N,N-dimethylformamide was stirred and refluxed for 17 hours. An additional 100 mg of potassium carbonate was added and stirring and reflux continued for 4 hours.
After cooling to room temperature, the mixture was carefully acidified to a pH value of 1 by addition of 1N hydrochloric acid. Water was added and the mixture was treated with ether in the usual manner. The residue was chromatographed on 50 g of silica gel.
Elution with 9:1 toluene-ethyl acetate gave racemic 6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro as a yellow oil. -2-Methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester 219 mg (52.6%)
I got it. Example 27 Using the method described in Example 4, a 191 mg sample of the product according to Example 26 was dissolved in lithium hydroxide-hydrate (273 mg) in 5 ml of 3:2 tetrahydrofuran-water.
saponified it. After column chromatography on silica gel, racemic 6 was obtained as a yellow viscous oil.
-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-
Propyl-2H-1-benzopyran-2-propanoic acid was obtained. Elemental analysis: Calculated for _C32H42O8 : C, 69.29; H, 7.63 Observed: C, 69.07; H, 7.79 Example 28 Using the method of Example 7, racemic 3,4 _- dihydro _- 6 A sample of 809 mg of the ethyl ester of -hydroxy-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid was dissolved in 4'-(3-bromopropoxy)-2'-hydroxy-3' in anhydrous dimethylformamide. -n-propylacetophenone 1.2
g, 448 mg of 50% sodium hydride-mineral oil dispersion and 1.2 g of sodium iodide. After saponification (1.2 g of lithium hydroxide hydrate), 1.6 g of crude crystalline acid was obtained. This material was chromatographed on 50 g of silica gel. 4:
Racemic 6-[3-(4-acetyl-3-hydroxy-2-propylphenophenol) was eluted with 1, 2:1 and 1:1 toluene-ethyl acetate as an off-white solid with a melting point of 144-147°C. C) Propoxy] -
3,4-dihydro-5,7,8-trimethyl-
2H-1-benzopyran-2-carboxylic acid 1.2g
(83.2%). Elemental analysis: Calculated for C ₂₇ H ₃₄ O ₇ : C, 68.92; H, 7.28 Actual: C, 68.68; H, 7.02 Example 29 25 g of p-benzyloxyphenol, 20 ml of freshly distilled acrolein, methanol A mixture of 70 ml and 0.5 ml of concentrated sulfuric acid was heated to 150° C. for 2 hours with stirring in a pressure bottle. The mixture was cooled and diluted with ether. The ethereal solution was washed with water and saturated sodium bicarbonate solution and worked up in the usual manner. Pour the brown oily residue (47.9g) into silica gel.
Chromatographed on 250g. 23.1 g of an orange oil eluted with toluene was obtained which was rechromatographed on 300 g of silica gel. Elution with 9:1-hexane-ethyl acetate yielded racemic 3,4-dihydro-2- as a yellow oil.
Methoxy-6-(phenylmethoxy)-2H-1-
12.8 g (37.9%) of benzopyran was obtained. This material was dissolved in 200 ml of acetone and 120 ml of 2N hydrochloric acid was added. The mixture was stirred and refluxed for 2 hours, stored at room temperature overnight, and refluxed for an additional 2 hours.
After cooling, the mixture was concentrated under water pump vacuum to remove most of the acetone. The aqueous residue was treated with ether in the usual manner (the combined ether extracts were further washed with saturated sodium bicarbonate solution) to give 12.1 g of a pale yellow solid. This material was chromatographed on 250 g of silica gel.
Racemic 3, eluted with 9:1 and 4:1 toluene-ethyl acetate as a pale yellow solid, mp 92-95°C.
4-dihydro-6-(phenylmethoxy)-2H-
1-benzopyran-2-ol 9.8g (80.7%)
I got it. Elemental analysis: Calculated for C ₁₆ H ₁₆ O ₃ : C, 74.98; H, 6.29 Observed: C, 74.78; H, 6.41 Example 30 Racemic 3,4-dihydro-6- in 20 ml of toluene
(Phenylmethoxy)-2H-1-benzopyran-
A solution of 1.8 g of 2-ol and 2.6 g of (carboxyethoxymethylene)triphenylphosphorane was added to the
Stir and reflux for an hour. Cool this solution and
It was placed in a column of 50 g of silica gel packed in toluene. Elution with toluene and 19:1 toluene-ethyl acetate gave 1.7 g (74.2
%) was obtained. This material was dissolved in 25 ml of absolute ethanol and the solution was stirred at room temperature in the presence of 0.2 g of 10% palladium on carbon under an atmosphere of hydrogen. After 1.5 hours, hydrogen absorption was complete and the catalyst was separated. The solution was concentrated in vacuo to give racemic 3,4-dihydro-6-hydroxy- as a pale yellow oil.
1.2 g (97.6%) of 2H-1-benzopyran-2-acetic acid ethyl ester was obtained. Example 31 Racemic 3,4-dihydro-6-hydroxy-
2H-1-benzopyran-2-acetic acid ethyl ester 1.2 g, 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone 1.8 g,
A mixture of 1.6 g of anhydrous potassium carbonate, 30 ml of dry acetone and 15 ml of dry dimethylformamide was stirred and refluxed for 23 hours. Additionally, 1.6g of potassium carbonate
was added and the mixture was stirred and refluxed for an additional 2.5 hours. After cooling, the mixture was carefully poured into 1N hydrochloric acid. Treatment with ether in the usual manner (the combined ether extracts were further washed with saturated sodium bicarbonate solution) gave 3.7 g of a brown oil, which was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate gave 1.6 g of a pale yellow oil. 1:1 tetrahydrofuran
A solution of the above ester and 3.0 g of lithium hydroxide hydrate in 40 ml of water was stirred at room temperature for 23 hours. The resulting solution was diluted with water and acidified to a pH value of 1 with 2N hydrochloric acid. Treatment with ether in the usual manner gave an oil which was chromatographed on 50 g of silica gel. Racemic 6-[3-(4-acetyl-
831 mg (37%) of 3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-acetic acid was obtained. Elemental analysis: Calculated for C ₂₅ H ₃₀ O ₇ : C, 67.86; H, 6.83 Found: C, 68.03; H, 6.75 Example 32 (Carboethoxymethylene) in 200 ml of toluene
17.5 g of triphenylphosphorane and 11.4 g of 4-benzyloxy-2-hydroxybenzaldehyde
The mixture was stirred and refluxed for 1 hour. After evaporation of the solvent under vacuum, 28.2 g of a residue was obtained, which contained (4'-benzyloxy-2'-hydroxy)benzenepropenoic acid ethyl ester and triphenylphosphine oxide.
Dissolve this material in ethyl acetate and add 0.35 g of platinum oxide.
Hydrogenation was carried out at atmospheric pressure and room temperature in the presence of . Separate the catalyst, concentrate the liquid under vacuum,
28.1 g of product containing (4'-benzyloxy-2'-hydroxy)benzenepropanoic acid ethyl ester
I got it. This material was treated with 100 ml of 5% methanolic potassium hydroxide solution and the mixture was refluxed for 2 hours. Most of the methanol was removed by concentration under vacuum and the residue was partitioned between ether and water. The etheric layer was abandoned. The aqueous phase was acidified with 2N hydrochloric acid and treated in the usual manner with 1:1 ether-tetrahydrofuran (4'-benzyloxy-2-
9.8 g of hydroxy)benzenepropanoic acid were obtained.
This material was dissolved in 98 ml of acetic anhydride and the solution was refluxed for 2 hours. After cooling, dissolve the solution in methanol.
100ml and the solvent was removed by concentration under vacuum. The methanol treatment and evaporation were repeated two more times and the residue was purified by high performance liquid chromatography on silica gel (eluent system 4:1 hexane-ethyl acetate). 6.2 g (48.8%) of 3,4-dihydro-7-(phenylmethoxy)-1-benzopyran-2-one was obtained as a solid. Example 33 3,4-dihydro-7 in 80 ml dichloromethane
-(phenylmethoxy)-1-benzopyran-2-
20 ml of diisobutylaluminum hydride (25% in toluene) at -76 °C to a stirred solution of 6.2 g of
was dripped. The reaction mixture was stirred at this temperature for 1 hour, then 5 ml of methanol were carefully added. The solution was poured into 25 ml of 1N sulfuric acid and the mixture was treated with ether in the usual manner (the combined organic extracts were further washed with saturated sodium bicarbonate solution). The residue (5.9 g) was purified by high performance liquid chromatography on silica gel (eluent system 3:1 hexane-ethyl acetate). 4.8 g (76.8%) of racemic 3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-ol was obtained as a colorless solid with a melting point of 64-65.5°C. Elemental analysis: _Calculated value for _C16H16O3 : C, 74.98; H, 6.29 Actual value: C, 74.44; H, 6.38 Example 34 Racemic 3,4-dihydro _- 7-(phenylmethoxy)-2H- A 2.2 g sample of 1-benzopyran-2-ol was treated with (carboethoxymethylene)triphenylphosphorane (3.2 g) using the method of Example 30.
It was condensed with. After purification by column chromatography, 2.6 g (92.8
%)was gotten. 0.2 g of 10% palladium on carbon as described in Example 30.
Hydrogenolysis was carried out above. Racemic 3,4 as pale yellow oil
1.9 g of -dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester was obtained. Example 35 Racemic 3,4-dihydro-7-hydroxy-
Sample 0.9 of 2H-1-benzopyran-2-acetic acid ethyl ester was prepared using the method described in Example 31.
4'-(3-bromopropoxy)-2'-hydroxy-
Alkylation was carried out with 3 g of 3'-n-propylacetophenone. Crude product (2.6 g) was dissolved in silica gel 50
chromatographed on g (eluting with 9:1 toluene-ethyl acetate) to give 1.2 g of the desired ester as a pale yellow oil. This material was converted into lithium hydroxide hydrate using the method described in Example 31.
Saponified at 2.0g. The crude acid (1.1 g) was chromatographed on 50 g of silica gel. 2:
1 and 1:1 toluene-ethyl acetate as a pale yellow solid with a melting point of 107-109.5°C.
[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-acetic acid 682 mg
(40.5%). Elemental analysis: Calculated for _C25H30O7 : C, _67.86 ; H, 6.83 Found: C, 68.07; H, 6.87 Example 36 6 _- Hydroxychromone-2- in 200 ml of acetic acid
A solution of 8.75 g of ethyl carboxylate was hydrogenated by shaking the suspension for 17 hours at 3.45 bar and room temperature in the presence of 2 g of 10% palladium on charcoal. pass through the catalyst,
The liquid was evaporated under reduced pressure to yield 7.85 g of crude material. This compound was purified by high performance liquid chromatography (solvent system, hexane-ethyl acetate 3:1) to give a crystalline pure racemic 3,4-dihydro-6-hydroxy-2H-1-benzopyran-
4.9 g (59%) of 2-carboxylic acid ethyl ester was obtained. Recrystallization from ethyl acetate-hexane gave a colorless solid with a melting point of 72-74°C. Elemental analysis: Calculated for _C12H14O4 : C, _64.85 ; H, 6.35 Found: C, 64.57; H, 6.45 Example 37 Racemic 6 _- hydroxychroman- in 30 ml of acetic acid
In a solution of 2.23 g of ethyl 2-carboxylate at 20-25℃
An air flow of boron trifluoride gas was introduced. During the gas introduction (30-45 minutes), a cold water bath was used to control the temperature of the exothermic reaction. The cooling bath was removed and the reaction mixture was heated to 80° C. for 5 hours; the reaction mixture was then cooled and carefully poured into a mixture of saturated sodium bicarbonate and ice, and the product was extracted with 1:1 tetrahydrofuran-ether. . The crude material obtained after evaporation of the solvent was chromatographed on a silica gel column and the racemic 7-acetyl-
6-hydroxy-3,4-dihydro-2H-1-
Benzopyran-2-carboxylic acid ethyl ester
1.6g (60%) was obtained. Example 38 Using the method described in Example 42, racemic 6-
Ethyl hydroxychroman-2-carboxylate 1.0
27.3g as a white crystalline substance with a melting point of 125-127℃
% yield of racemic 6-[3-(4-acetyl-3
-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. Elemental analysis: _Calculated for _C24H28O7 : C, _67.28 ; H, 6.59 Actual value: C, 67.27; H, 6.67 Example 39 Racemic 7-acetyl-6-hydroxychroman-2-carboxylic acid ethyl ester 1.6 g, potassium carbonate 3.0g, 1,3-dibromopropane 5ml,
60ml dry acetone and dry dimethylformamide
The 30ml mixture was stirred and refluxed for 20 hours. After removing most of the solvent under vacuum, the residue was diluted with ether and carefully treated with 1N hydrochloric acid. The organic phase was separated, washed with saturated sodium bicarbonate solution and water, dried and concentrated under vacuum. Crude bromopropyl derivative (2.1g) was dissolved in acetone.
Dissolved in 30 ml, 1.2 g of 2',4'-dihydroxy-3'-propylacetophenone, 2.5 g of anhydrous potassium carbonate.
g, 30 ml of dry acetone and dimethylformamide
Added to 30ml of mixture. The reaction mixture was gently refluxed for 25 hours. After removing most of the solvent, the product was extracted with ether, the ether extract was washed with brine, and dried. The crude material obtained after evaporation of the solvent (3.1 g) was chromatographed on silica gel to yield 1.3 g of the desired ester.
(43%). This material was dissolved in an aqueous solution of lithium hydroxide (lithium hydroxide hydrate in 18 ml of water).
2.2g) for hydrolysis. The cloudy reaction mixture was stirred at room temperature for 21 hours, poured into 1N hydrochloric acid, and the product was extracted with ether. The organic phase was washed with brine, dried and evaporated to give 1.2 g of a viscous yellow oil. It was purified by chromatography on a silica gel column as a white crystalline substance with a melting point of 140.5-142.5°C (crystals from ethyl acetate). propylphenoxy)propoxy]-3,
0.778 g (27.3%) of 4-dihydro-2H-1-benzopyran-2-carboxylic acid was obtained. Elemental analysis: _Calculated value for _C26H30O8 : C, _66.37 ; H, 6.43 Actual value: C, 66.44; H, 6.51 Example 40 Using the hydrogenation conditions described in Example 36, 7-
Ethyl hydroxychromone-2-carboxylate 1.09
g was converted to ethyl cerami 7-hydroxychroman-2-carboxylate in a yield of 53% as a crystalline material with a melting point of 81-82.5°C (crystalline from ethyl acetate-hexane). Elemental analysis: Corresponds to C ₁₂ H ₁₄ O ₄ Calculated value: C, 64.85; H, 6.35 Actual value: C, 64.60; H, 6.26 Example 41 1.1 g sample of racemic ethyl 7-hydroxychromone-2-carboxylate was treated with 10 ml of 1:1 acetic anhydride-pyridine and stirred at room temperature for 17 hours. After removal of the solvent, the remaining product (1.2 g) was dissolved in 12 ml of glacial acetic acid.
and treated with 1.26 ml of boron trifluoride etherate. The reaction mixture was gently refluxed for 17 hours,
Cool, carefully pour into a mixture of sodium bicarbonate and ice, and dissolve the product in a 1:1 tetrahydrofuran solution.
Extracted with ether. After evaporation of the solvent, the crude racemic 7-hydroxy-6-acetylchroman-2-
1.1 g of carboxylic acid was obtained. Conversion of this material to the corresponding ethyl ester required 1.1 g of the crude acid.
was achieved by refluxing in p-toluene in absolute ethanol for 17 hours in the presence of 10 mg p-toluenesulfonic acid. After removing most of the solvent, the product was extracted with 1:1 tetrahydrofuran-ether, washed with saturated sodium bicarbonate solution, water, dried, the solvent was concentrated, and 6-acetyl 1.2 g of crude ethyl ester was obtained as a mixture of and 8-acetyl derivative. This material was purified by column chromatography on silica gel as a colorless crystalline material with a melting point of 93.5-95.5°C (crystals from ethyl acetate-hexane), racemic 6-acetyl-3,4-dihydro-7-
0.7 g (53.5%) of hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester was obtained. Example 42 1 g of racemic ethyl 7-hydroxychroman-2-carboxylate, 4'-(3-bromopropoxy)-
2'-Hydroxy-3'-propylacetophenone 1.6
A mixture of 1.6 g of anhydrous potassium carbonate, 25 ml of acetone and 12 ml of dimethylformamide was stirred and refluxed for 23 hours. After cooling, 1N hydrochloric acid was carefully added and the product was extracted with ether. The ether layer was washed with brine, dried and evaporated under vacuum to give 3.6 g of an orange oil. Chromatographically purified and alkylated ethyl ester on silica gel
1.4g was obtained. Add this substance to tetrahydrofuran20
ml, treated with aqueous lithium hydroxide solution (2.6 g of lithium hydroxide hydrate in 20 ml of water) and stirred at room temperature for 23 hours. The reaction mixture was made acidic and the product was extracted with ether, washed with brine and dried. Removal of the solvent gave 1.3 g of pale yellow acid, which was purified on a silica gel chromatographic column to give racemic 7-[3-(4-acetyl- 0.554 g (28.7%) of 3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was obtained. Elemental analysis: Calculated for _C24H28O7 : C, _67.28 ; H, 6.59 Observed: C, 67.34; H, 6.62 Example 43 Using the method of Example 39, racemic 6 _- acetyl-7-hydroxy 0.840 g of ethyl chroman-2-carboxylate as a colorless solid with a melting point of 178.5°C (decomposed) (crystallized from ethyl acetate) in a yield of 49.5%.
Racemic 6-acetyl-7-[3-(4-acetyl-
It was converted to 3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. Elemental analysis: _Calculated value for _C26H30O8 : C, _66.37 ; H, 6.43 Actual value: C, 66.27; H, 6.39 Example 44 Using the hydrogenation conditions described in Example 36, 7-
5.52 g of ethyl hydroxy-8-propylchromone-2-carboxylate as a viscous pale yellow oil
% yield to racemic ethyl 7-hydroxy-8-propylchromone-2-carboxylate. Example 45 Using the method described in Example 41, racemic 3,4
-dihydro-7-hydroxy-8-propyl-
1.3 g of 2H-1-benzopyran-2-carboxylic acid ethyl ester was prepared as a viscous oil with a yield of 79.5%.
Converted to the corresponding 6-acetyl derivative. Example 46 Using the method described in Example 42, racemic 7-
1.0 g of hydroxy-8-propylchroman-2-carboxylic acid ethyl ester was converted into racemic 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) as a pale yellow solid with a melting point of 105-107°C.
[propoxy]-3,4-dihydro-8-propyle-2H-1-benzopyran-2-carboxylic acid. Elemental analysis: _Calculated value for _C27H34O7 : C, _68.92 ; H, 7.28 Actual value: C, 69.06; H, 7.29 Example 47 Racemic 6-acetyl-7-hydroxy-8-propylchroman-2-carvone ethyl acid 0.85g,
A mixture of 1.2 g of anhydrous potassium carbonate, 2.3 ml of 1,3-dibromopropane, 0.1 g of 18-crown-6-ether and 20 ml of acetonitrile was refluxed for 23 hours. After cooling, the reaction mixture was diluted with ether.
The organic phase was washed with brine, dried and evaporated to give 1.2 g of bromopropyl derivative as a yellow oil. This bromide was prepared by alkylation of 2',4'-dihydroxy-3'-propylacetophenone followed by saponification using the conditions described in Example 39.
In an overall yield of about 40%, racemic 6-acetyl-7-[3-(4-acetyl-3-hydroxy-2
-propylphenoxy)propoxy]-3,4-
It was converted to dihydro-8-propyl-2H-1-benzofuran-2-carboxylic acid. This acid has a melting point
Obtained as a colorless solid of 108-110.5° (crystals from ethyl acetate-hexane). Elemental analysis: _Calculated value _{for C26H36O8} : C, 67.95; H, 7.08 Actual value: C, 68.16; H, 7.20 Example 48 Using the method described in Example 39, with the exception of 1,3-
By replacing dibromopropane with 1,5-dibromopentane, racemic 6-acetyl-7-hydroxy-
3,4-dihydro-2H-1-benzopyran-2
-Carboxylic acid ethyl ester, melting point 113-115℃
racemic 6-acetyl-7 in 32.8% yield as a colorless solid (crystallized from ethyl acetate-hexane).
-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-
It was converted to dihydro-2H-1-benzopyra-2-carboxylic acid. Elemental analysis: _Calculated value for _C28H34O8 : C, _67.45 ; H, 6.87 Actual value: C, 67.61; H, 6.80 Example 49 Using the method described in Example 39, with the exception of 1,3-
By replacing dibromopropane with 1,7-dibromoheptane, racemic 6-acetyl-7-hydroxy-
3,4-dihydro-2H-1-benzopyran-2
-carboxylic acid ethyl ester, overall yield 39.1
%, racemic 6-
It was converted to acetyl-7-[7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. Elemental analysis: Corresponds to C ₃₀ H ₃₈ O ₈ Calculated: C, 68.42; H, 7.27 Observed: C, 68.22; H, 7.19 Example 50 Using the method described in Example 39, racemic 8-acetyl -7-hydroxy-3,4-dihydro-
0.62 g of 2H-1-benzopyran-2-carboxylic acid ethyl ester was prepared in an overall yield of 27.7%.
Racemic 8-acetyl-7-[3-(4-acetyl-3-hydroxy-2
-propylphenoxy)propoxy]-3,4-
It was converted to dihydro-2H-1-benzopyran-2-carboxylic acid. Elemental analysis: Calculated value for C ₂₆ H ₃₀ O ₈ : C, 66.37; H, 6.43 Actual value: C, 66.51; H, 6.47 Example 51 Using the method described in Example 37, racemic 3,4
-dihydro-6-hydroxy-2-methyl-2H
- 0.125 g of sample of 1-benzopyran-2-carboxylic acid ethyl ester was converted into a viscous oil with a yield of 65.5%.
and racemic 3,4-dihydro-7-acetyl-6
-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester. Example 52 Using the method described in Example 39, racemic 3,4
-dihydro-7-acetyl-6-hydroxy-2
A 96.5 ml sample of -methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester was prepared as a foam in 65.7% yield of racemic 7-acetyl-6-[3
-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid. Example 53 4-benzyloxy-2-hydroxybenzaldehyde 1.14 g, 1,4-diazabicyclo[2.2.2]
A mixture of 0.125g octane and 0.65g acrylonitrile was heated to 80-85°C for 2 hours under argon. After removal of the solvent, the remaining product was dissolved in tetrahydrofuran-ether (1:1), washed with 1N sodium hydroxide, water, dried and the solvent was evaporated under vacuum. The crude material (1.10 g) was purified by column chromatography on silica gel,
Melting point: 95-95℃ (crystals from ethyl acetate-hexane)
7-(phenylmethoxy)- as a colorless solid of
2H-1-benzopyran-3-carbonitrile 0.6
g (45.7%). Elemental analysis: Calculated value _{for C17H13NO2} : C, _77.55 ; H, 4.95; N, 5.32 Actual value: C, 77.41; H, 5.00; N, 4.80 Example 54 Tetrahydrofuran-ethyl alcohol (1:
7-(phenylmethoxy) dissolved in the mixture of 1)
2.2 g of a sample of -2H-1-benzopyran-3-carbonitrile was treated with 20 ml of 2N potassium hydroxide,
The reaction mixture was refluxed under argon for 21 hours. Add another 10ml of 2N potassium hydroxide and stir the mixture further.
Stir and reflux for 27 hours. Reaction mixture 1N
Acidified with hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and the solvent was evaporated under vacuum to give 2.2 g of an orange solid. p-Toluenesulfonic acid hydrate
A solution of 0.3 g of the above material in 30 ml of ethanol was refluxed under argon for 18 hours. After removing most of the solvent, the remaining product was extracted with ether, the extract was washed with saturated sodium bicarbonate solution, water, dried and the solvent was evaporated to give 2.3 g of the crude ethyl ester. Purification by chromatography on a silica gel column gave 1.4 g of 7-(phenylmethoxy)-2H-1-benzopyran-3-carboxylic acid ethyl ester as a crystalline substance. Example 55 The ester according to Example 54 (1.4 g) was dissolved in 25 ml of absolute alcohol and hydrogenated at atmospheric pressure in the presence of 0.2 g of 10% palladium on charcoal. the catalyst is removed by passing it over diatomaceous earth;
After removal of the solvent, 0.9 g of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-3-carboxylic acid ethyl ester was obtained as a white solid. Example 56 The ethyl ester according to Example 55 was prepared using the method described in Example 42 in an overall yield of 17.7%.
Racemic 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,
It was converted to 4-dihydro-2H-1-benzopyran-3-carboxylic acid. This acid has a melting point of 153.5-155.5
Obtained as a colorless solid (crystals from ethyl acetate-hexane). Elemental analysis: Calculated for _C24H28O7 : C, _67.28 ; H, 6.59 Found: C, 67.49; H, 6.66 Example 57 Racemic 7 _- hydroxy-3,4-dihydro-2H dissolved in 5 ml of pyridine -1-benzopyran-
A 0.9 g sample of 3-carboxylic acid ethyl ester was treated with 1.2 ml of acetic anhydride. After stirring for 3 hours at room temperature, the reaction mixture was diluted with ether. The organic layer was washed with 2N hydrochloric acid, sodium bicarbonate, water, dried and the solvent was evaporated. crude acetate 1.2
g was obtained, which was dissolved in 10 ml of glacial acetic acid and treated with 1 ml of boron trifluoride etherate. The reaction mixture was heated to 100° C. for 6 hours under argon.
After cooling, ether was added. The organic layer was washed several times with water, dried, and the solvent was evaporated under vacuum to an orange oil.
1.0g was obtained. Esterification of this material with ethanol was performed as described in Example 41 to yield racemic 6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester. Example 58 Using the method described in Example 39, racemic 6-acetyl-7-hydroxy-3,4-dihydro-
2H-1-Benzopyran-3-carboxylic acid ethyl ester was converted into racemic 6-acetyl-7-[3-(4-
Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1
-benzopyran-3-carboxylic acid. The acid product was a colorless solid with a melting point of 127-129°C (decomposition) (crystallized from ethyl acetate-hexane). Elemental analysis: Calculated for _C26H30O8 : C, _66.37 ; H, 6.43 Observed: C, 66.45: H, 6.43 Example 59 Using the method described in Example 41, racemic 7 _- hydroxy-3 ,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester 11.3g
was converted to crude racemic 7-hydroxy-6-acetyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 93% yield (11 g). A sample of 1 g of this crude acid was placed in the presence of 0.2 g of p-toluenesulfonic acid hydrate.
Treated with 3.8 g of (-)-(2R,3R)-butanediol in 30 ml of toluene. After refluxing for 18 hours, the reaction mixture was cooled, poured into a saturated solution of sodium bicarbonate, and the product was extracted with ether. The ether extract was washed twice with water, dried and concentrated.
After removal of the solvent, 1.8 g of crude product was obtained, which was a mixture of 6-acetyl and 8-acetyl monobutanediol ester derivatives in a ratio of about 7:1. This material was purified by HPL as a viscous pale yellow oil [2R,S-2-
[1R ^* , 2R ^* )]-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-
0.8 g (61%) of 2-carboxylic acid 1-methyl-2-hydroxypropyl ester was obtained. Example 60 Using the method described in Example 25, acetone 100
ml and [2R,S-2-[1R ^* ,2R ^* )]-6-acetyl- in 50 ml of N,N-dimethylformamide.
7-hydroxy-3,4-dihydro-2H-1-
1-Methyl-2-benzopyran-2-carboxylate
From 3.5 g of hydroxypropyl ester, 12 ml of 1,5-dibromopentane, and 7.2 g of anhydrous potassium carbonate, [2R,S-2-[(1R ^* ,R2 ^* )]-6-acetyl-7-[(5-bromopentyl )oxy]-3,
2.6 g (50%) of 4-dihydro-2H-1-benzopyran-2-carboxylic acid 2-hydroxy-1-methylpropyl ester was obtained. Next, this substance
The less polar diastereoisomer, separated by HPLC (toluene-ethyl acetate 2:1) and recycled, was recrystallized from ethyl ether as a colorless solid [2S-[2β(1R ^* ,2R ^* )]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,
786 mg of 4-dihydro-2H-1-benzopyran-2-carboxylic acid 2-hydroxy-1-methylpropyl ester was obtained, melting point 94.5-98°; [α] ²⁵ ₂ −
7.99° (c1, _CHCl3 ). Elemental analysis: Calculated for C ₂₁ H ₂₉ BrO ₆ : C, 55.15; H, 6.39 Observed: C, 54.79; H, 6.20 The more polar diastereoisomer was recrystallized from ethyl ether as a colorless solid. [2R] [2α
(1R ^* ,2R ^* )]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-
1-benzopyran-2-carunic acid 2-hydroxy-1-methylpropyl ester (melting point 80-83°C;
[α] ²⁵ _D −24.49° (c1, CHCl ₃ )] 1.03 g was obtained. Elemental analysis: _Calculated value for _C21H20BrO6 : C, 55.15; H, 6.39 Actual value: C, 55.06 _; H, 6.39 Example 61 Using the method described in Example 26, [2S-[2β
(1R ^* ,2R ^* )]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-
199.8 ml of 1-benzopyran-2-carboxylic acid-hydroxy-1-methylpropyl ester was added to 2',4'-
Alkylation was performed with dihydroxy-3'-n-propylacetophenone. After chromatographic purification on a silica gel column, [2S−[2β(1R ^* ,2R ^* )]]
-6-acetyl-7-[5-(4-acetyl-3-
106 ml (42.8%) of hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 2-hydroxy-1-methylpropyl ester were obtained.
[α] ^25/ −7.25° (c1, CHCl ₃ ); (melting point 124-127.5°C
)
(Recrystallized from ethyl acetate-hexane). Elemental analysis: _Calculated value _{for C32H42O9} : C, 67.35; H, 7.42 Actual value: C, 67,14; H, 7.51 Example 62 2R according to Example 60 using the method of Example 61
-Bromoester 554 mg in 72.6% yield [2R-(2α(1R ^* ,2R ^* )]-6-acetyl-7-(5
-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 2-hydroxy-1-methylpropyl ester [ Melting point 100~105℃; [α] ²⁵ _D −15.75° (c1,
CHCl ₃ ); ethyl acetate-hexane crystals]. Elemental analysis: Calculated for C ₃₂ H ₄₂ O ₉ : C, 67.35: H, 7.42 Observed: C, 66.98: H, 7.39 Example 63 Sample 405 of 2S-isomeric ester according to Example 61
mg of lithium hydroxide in 10 ml of 1:1 tetrahydrofuran-water using the method described in Example 4.
Saponified with hydrate. After crystallization from ethyl acetate-hexane, (S)-6-acetyl-7-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid, melting point 94-
97.5℃: [α] ²⁵ _D +1.25° (c1, CHCl ₃ ), 185 mg (52.
2
%)was gotten. Elemental analysis: _Calculated value for _C28H34O8 : C, _67.45 ; H, 6.87 Actual value: C, 66.60: H, 6.70 Example 64 2R according to Example 62 using the method of Example 63
- From 502 mg of isomeric ester, after crystallization from ethyl acetate-hexane, (R)-6-acetyl-7-
[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid
Obtained 185 mg (40.7%), 102.5-108 °C, [α] ²⁵ _D −
1.02° (c1, _CHCl3 ). Elemental analysis: Calculated value for _C28H34O8 : C, _67.45 ; H, 6.84 Actual value: C, 67.26; H, 6.78 Example 65 Racemic 3,4 _- dihydro-7-hydroxy-2H
-1-benzopyran-2-carboxylic acid ethyl ester 1 g (4.5 mmol), 1,5-dibromopental 3.7 ml (27.2 mmol), anhydrous potassium carbonate 2
g (14.5 mmol), 30 ml of acetone and N,N-
A mixture of 15 ml of dimethylformamide was stirred and refluxed for 20 hours. The mixture was cooled and diluted with ether. The ether solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered,
It was then concentrated under reduced pressure to obtain 7.2 g of a yellow liquid.
This material was chromatographed on 50 g of silica gel. Racemic 7-[(5-
Bromopentyl[oxy]-3,4-dihydro-
1.2 g (72%) of 2H-1-benzopyran-2-carboxylic acid ethyl ester was obtained. Example 66 Using the method and molar proportions of Example 65, the following compounds were prepared from the starting materials shown. All compounds were purified by chromatography on silica gel and isolated as pale yellow oil: racemic 6-acetyl-7-hydroxy-3,4
-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5
- from dibromopentane, racemic 6-acetyl-7-[(5-bromopentyl)oxy]-3,4
-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-3,4-dihydro-7-
From hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5-dibromopentane, racemic 6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-3,4-dihydro-7-
From hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,6-dibromohexane, racemic 6-acetyl-7-[(6-bromohexyl)oxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-3,4-dihydro-7-
From hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,4-dibromobutane, racemic 6-acetyl-7-[(4-bromobutyl)oxy]-3,4-dihydro-2H-1
-Benzopyran-2-carboxylic acid ethyl ester. Racemic 3,4-dihydro-7-hydroxy-8
From -propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5-dibromopentane, racemic 7-[(5-bromopentyl)
Oxy]-3,4-dihydro-8-propyl-2H
-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 8-acetyl-3,4-dihydro-7-
From hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester and 1,5-dibromopentane, racemic 8-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid methyl ester. Example 67 Racemic 7-[(5-bromopentyl)oxy]-3,
1.2 g (3.23 mmol) of 4-dihydro-2H-1-bezonpyran-2-carboxylic acid ethyl ester,
2',4'-dihydroxy-3'-propylacetophenone 1.0 g (5.15 mmol), anhydrous potassium carbonate 1.8
g (13.0 mmol), 30 ml of acetone and N,N-
A mixture of 15 ml of dimethylformamide was stirred and refluxed for 6 hours. After cooling, the mixture was diluted with ether. The ether phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Pour the residue (21g) into 50ml of silica gel.
Chromatography was carried out at g. Racemic 7 was eluted with 19:1 toluene-ethyl acetate as a yellow oil.
-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-
1.3 g (83%) of dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester was obtained. Example 68 Using the method and molar proportions of Example 67, the following compounds were prepared from the starting materials shown. All compounds were purified by chromatography on silica gel and isolated as pale yellow oils. Racemic 6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2',4'-dihydroxyacetophenone from, racemic 6-acetyl-7-[5-(4-
Acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-8-propyl-2H
-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-7-[(5-bromopentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester and
From 2',4'-dihydroxyacetonephenone, racemic 6-acetyl-7-[5-(4-acetyl-3
-hydroxyphenoxy)pentyloxy]-3,
4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester. Lacecyl 6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2',4'-dihydroxy-3' -From propylacetophenone, racemic 6-acetyl-
7-[5-(4-acetyl-3-hydroxy-2-
Propylphenoxy)pentyloxy]-3,4
-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 7-[(2-bromopentyl)oxy]-
3,4-dihydro-2H-1-benzopyran-2
- from carboxylic acid ethyl ester and 2',4'-dihydroxyacetonephenone, racemic 7-[5-
(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-7-[(6-bromohexyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester and
From 2',4'-dihydroxy-3'-propylacetophenone, racemic 6-acetyl-7-[6-(4-
Acetyl-3-hydroxy-2-propylphenoxy)hexyloxy]-3,4-dihydro-2H
-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 6-acetyl-7-[(4-bromobutyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester and
From 2',4'-dihydroxy-3'-propylacetophenone, racemic 6-acetyl-7-[4-(4-
Acetyl-3-hydroxy-2-propylphenoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 7-[(5-bromopentyl)oxy]-
3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and
From 2',4'-dihydroxyacetophenone, racemic 7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-
8-Propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 7-[{5-bromopentyl)oxy]-
3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and
From 2',4'-dihydroxy-3'-propylacetophenone, racemic 7-[5-4-acetyl-3-
Hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydroxy-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester. Racemic 8-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester and
From 2',4'-dihydroxy-3'-propylacetophenone, racemic 8-acetyl-7-[[5-(4
-Acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester. Example 69 1.3 g (2.68 mmol) of the ester product according to Example 67, 60 ml of 1:1 tetrahydrofuran-water and 2.4 g (57.1 mmol) of lithium hydroxide hydrate.
The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water and extracted three times with ether. water phase
The mixture was acidified to a pH value of 1 with 2N HCl and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give racemic 7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro as a colorless solid with a melting point of 124-126.5°C. 0.725 g of -2H-1-benzopyran-2-carboxylic acid was obtained. Elemental analysis: Calculated value for C ₂₆ H ₃₂ O ₇ : C, 68.40; H, 7.07 Actual value: C, 68.34; H, 7.29 Example 70 Using the method and molar proportions of Example 69, Example 70
The acids shown in the following table were prepared by saponifying the corresponding esters according to 68:

[Table] A=(racemic)6-acetyl-7-[5-(4-acetyl)-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-8-propyl-2H-1-benzopyran- 2-Carboxylic acid B = (racemic)6-acetyl-7-[5-(4-acetyl)-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-2H-1benzopyran-2-carboxylic acid C=(racemic)6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-
8-propyl-2H-1-benzopyran-2-
Carboxylic acid D=(racemic)7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,
4-dihydro-2H-1-benzopyran-2-
Carboxylic acid E = (racemic) 6-acetyl-7-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexoxy]-3,4-dihydro-2H
-1-Benzopyran-2-carboxylic acid F=(racemic)6-acetyl-7-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-3,4-dihydro-2H- 1
-Benzopyran-2-carboxylic acid G=(racemic)7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-8-propyl-
2H-1-Benzopyran-2-carboxylic acid H=(racemic)7-[5-4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-8-propyl-
2-H-1-benzopyran-2-carboxylic acid I = (racemic) 8-acetyl-7-[[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid Example 71 (R)-(+)-6-hydroxy-3 ,4-dihydro-2,5,7,8-tetramethyl-2H-1-
Benzopyran-2-carboxylic acid methyl ester
6.2g (24.6mmol), anhydrous potassium carbonate 10.37g
(75.1 mmol), 18-crown-6 (18-crown
-6) 1.12g, 1.5-dibromopentane 39.3ml
(0.2 mol) and 150 ml of acetonitrile.
Stir and reflux for 21 hours. After cooling, the mixture was treated with ether and water. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was first column chromatographed on silica gel (400 g; liberated with 49:1 toluene-ethyl acetate);
It was then purified by preparative HPLC on silica gel using 9:1 hexane-ethyl acetate as the mobile phase. (R)-(+)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2, as a solid;
5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester 9.71g
(95.6%) was obtained. Recrystallized from ethanol,
A colorless solid was obtained, melting point 64-65.5°C, [α] ²⁵ _D +
36.37° (c2, _CHCl3 ). Elemental analysis; Calculated value _{for C20H29BrO4} : C, 58.12; _7.07 ; Br, 19.33 Actual value: C58.01; H, 7.07; Br, 19.20 Example 72 Using the method and molar proportions of Example 71 , (S)-
(-)-6-hydroxy-3,4-dihydro-2,
5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester
Alkylated with dibromopentane to give (S)-(-)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7, in 88.5% yield.
8-tetramethyl-2H-1-benzopyran-2
-Carboxylic acid methyl ester obtained, [α] ²⁵ _D +
34.60° (c2, _CHCl3 ). Elemental analysis: _Calculated value for _C20H29BrO4 : C, 58.12; _H7.07 ; Br, 19.33 Actual value: C, 58.00; H, 7.19; Br, 19.33 Example 73 The method and molar ratio of Example 71 racemic 6-hydroxy-3,4-dihydro-2,5,
1 g of 7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was mixed with 1,5-
After alkylation with dibromopentane and purification by chromatography on silica gel, 90%
racemic 6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran as a colorless solid with a melting point of 72.5-74.5°C in a yield of 7-2-carboxylic acid methyl ester was obtained. Elemental analysis: Calculated value _{for C20H29BrO4} : C, 58.12; H, 7.07; Br, 19.33 Actual value: C, 58.13; H, 7.15; Br, 19.30 Example 74 (R) _- ( according to Example 71 +)-bromo-ester product 7.35 g (17.8 mmol), 2',4'-dihydroxy-3'-propylacetophenone 3.85 g
(19.8 mmol), anhydrous potassium carbonate 8.93 g (64.7
mmol), 154 ml of dry acetone and dry N,N-
A mixture of 77 ml of dimethylformamide was stirred and refluxed for 5.5 hours. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 10.8 g of an oil. This material was purified by preparative HPLC on silica gel using 2:1 hexane-ethyl acetate as the mobile phase. (R)-(+)-6-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,
5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester 9.1 g (97
%) was obtained, [α] ²⁵ _D +26.62° (c2, CHCl ₃ ). Elemental analysis: Calculated value _{for C31H31BrO7} : C, _70.70 ; H, 8.04 Actual value: C, 70.06; H, 8.18 Example 75 Using the method of Example 74, (S)- according to Example 72 (-)-Bromo-ester product (8.4g)
by alkylation of 2',4'-dihydroxy-3'-propylacetophenone (4.4 g) to (S)-(-)-6-[5-(4-acetyl -3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,
It was converted to 5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester. This material was a yellow oil. Elemental analysis: Calculated for C ₃₁ H ₄₂ BrO ₇ : C, 70.70; H, 8.04 Observed: C, 70.13; H, 7.73 Example 76 Using the method and molar proportions described in Example 74,
Racemic bromo-ester product according to Example 73
By alkylation of 1.2 g with 2′,4′-dihydroxy-3′-propylacetophenone (0.834 g),
Racemic 6-[5-(4
-Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydroxy-2,5,7,8-tetramethyl-2H-1-
It was converted to benzopyran-2-carboxylic acid methyl ester. Elemental Analysis: Calculated _{for C31H42O7} : C, _70.70 ; H, 8.04 Found: C, 70.44; H, 7.97 Example 77 (R)-(+)-ester product according to Example 74
7.55 g (14.3 mmol), tetrahydrofuran 140
ml, 90 ml of water and 12.6 ml of lithium hydroxide hydrate
(0.21 mol) was stirred at room temperature for 7 hours and kept at 0° C. for 17 hours. Cool the mixture with 3N HCl
I poured it inside. The organic material was extracted three times with ethyl acetate. Combine the extracts, wash with water and saturated brine,
Dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Remaining yellow glass (7.3g)
was chromatographed on 350 g of silica gel. Elution with 4:1, 2:1 and 1:1 toluene-ethyl acetate gave the desired acid (5 g) which was recrystallized from acetonitrile. (R)-(+)-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)] as a colorless solid
pentyloxy]-3,4-dihydro-2,5,
2.49 g (34%) of 7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid was obtained, melting point
92.5-95°C, [α] ²⁵ _D +37.86° (c2, _CHCl3 ). Elemental analysis: _Calculated value _{for C30H40O7} : C, 70.29; H, 7.87 Actual value: C, 70.25; H, 7.92 Example 78 Using the method of Example 77, (S)- according to Example 75 9.35 g (17.8 mmol) of the (-)-ester product was saponified. After recrystallization from acetonitrile, (S)-(-)-6-[5-
(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-
Obtained benzopyran-2-carboxylic acid, melting point 90~
93.5℃, [α] ²⁵ _D +38.18° (c2, CHCl ₃ ). Elemental Analysis: Calculated for C ₃₀ H ₄₀ O ₇ : C, 70.29; H, 7.87 Found: C, 70.50; H, 8.11 Example 79 5.8 g of racemic ester according to Example 76 using the method of Example 77 (11 mmol) was saponified.
Racemic 6- as a colorless solid with a melting point of 92.5-95°C
[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-
2.77 g of 1-benzopyran-2-carboxylic acid (49
%) was obtained. Elemental analysis: Calculated value for _C30H40O7 : C, _70.29 ; H, 7.87 Actual value: C, 70.28; H, 7.98 Example 80 Racemic 6 _- acetyl-7-[5-(4-acetyl-
A mixture of 2 g (4 mmol) of 3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 155 ml of water was mixed with 40 ml of 0.1N aqueous sodium hydroxide solution ( 4 mmol). The mixture was stirred at room temperature for 2 hours and then filtered off with suction. The liquid was lyophilized to give a solid residue, which was dissolved in hot ethyl acetate containing a small amount of ethanol, and hexane was added to form a precipitate. This mixture was heated to 0°C.
It was stored overnight and then aspirated. The solid was washed with ethyl acetate-hexane (2:1) and the recrystallized product was isolated. Monosodium salt of the starting acid as a colorless solid after drying at 60 °C under high vacuum
1.6g (77%) was obtained. _Elemental analysis: Calculated for _C28H33NaO3 : C, _64.61 ; H, 6.39; Na, 4.42 Observed: C, 64.50; H, 6.55; Na, 4.17 Example 81 Racemic 6-acetyl- in 15 ml of ethanol 7-
Add 4 ml of ether to a solution of 2 g (4 mmol) of [5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. 0.242g of d-(+)-α-methylbenzylamine in
(2 mmol) was added. The resulting solution was diluted with 10 ml of ether and stored at 0°C. The precipitate was filtered off with suction and washed with ether. Recrystallized from ethanol as a colorless solid with a melting point of 167-170°C 0.742
g (60%) was obtained, which was mainly the d-amine salt of the (S)-acid. This salt was suspended in ethyl acetate and shaken with 1N HCl. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
As a solid (S)-6-acetyl-7-[5-(4
-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-
2H-1-benzopyran-2-carboxylic acid 0.58g
was gotten. This material feed was esterified with diazomethane. The resulting methyl ester is
It was analyzed for enantiomeric composition by liquid chromatography on a 30 cm Prikle covalent phenylglycine column. This analysis showed that the acid obtained by this resolution method consisted of 95.3% of the (S)-enantiomer (less polar methyl ester) and 4.7% of the (R)-enantiomer (more polar methyl ester). Ta. Example 82 Racemic 3,4-dihydro- in 100 ml of acetone
7-Hydroxy-2H-1-benzopyran-2-
6 g (27 mmol) of carboxylic acid ethyl ester,
A mixture of 6.8 g (54 mmol) benzyl chloride, 7.5 g (54 mmol) anhydrous potassium carbonate and 4.5 g (27 mmol) potassium iodide was stirred and refluxed for 7 hours. Most of the acetone was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil 17.4
I got g. This material was chromatographed on silica gel. Elution with 19:1 toluene-ethyl acetate gave 6.9 g (78
%) was obtained. Example 83 Ether ester product according to Example 82 (6.9
g, 22 mmol) was dissolved in 70 ml of toluene and the solution was cooled to -78°C (dry ice-acetone bath). 15.6 ml of a 25% solution of diisobutylaluminum hydride in toluene was added dropwise with stirring. The reaction mixture was stirred at −78° C. for 2 hours, then 2.5 ml of methanol was carefully added, followed by 2 NCl and ice. The mixture was extracted with ethyl acetate and the organic extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (7.6 g) was chromatographed on silica gel. Elution with 9:1 toluene-ethyl acetate gave 5.6 g (70%) of racemic 3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-carboxaldehyde as a pale yellow oil.
I got it. Example 84 Using the method of Example 30, 2.7 g (1.0 mmol) of the aldehyde product according to Example 83 was added to 30 g of toluene.
ml (carboethoxymethylene)triphenylphosphorane (10.6 mmol) (1.5 h at 100° C.). After chromatography of the crude product on 50 g of silica gel (eluting with toluene) racemic 3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-propenoic acid was obtained as a pale yellow oil. Ethyl ester (E
- and Z-isomer mixture) 3.0 g (88.8%) were obtained. Example 85 Propenoic acid ester product according to Example 84 (3
g; 8.9 mmol) was hydrogenated over 0.3 g of 10% palladium on carbon in ethyl acetate (35 ml) at atmospheric pressure and room temperature, and after evaporation of the catalyst the racemic 3,4 -dihydro-7-
2.4 g of hydroxy-2H-1-benzopyran-2-propanoic acid ethyl ester was obtained. Example 86 Using the method of Example 41, the propanoic acid ester product according to Example 85 was converted to racemic 6-acetyl-
3,4-dihydro-7-hydroxy-2H-1-
Benzopyran-2-propanoic acid ethyl ester
1.4 g (54%) was converted; this was a yellow oil obtained after chromatography on silica gel (eluted with 19:1 toluene-ethyl acetate) and crystallized on standing. Example 87 Using the method of Example 65, the acetylpropanoate ester product according to Example 86 (1.4 g, 4.79 mmol) was converted into racemic 6-acetyl-7- in 76% yield (1.6 g) as a yellow oil. Converted to [(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-propanoic acid ethyl ester; this oil crystallized on standing (chromatographed on silica gel). Purified by elution with 19:1 toluene-ethyl acetate). Example 88 Using the method of Example 67, the bromoester product according to Example 87 (1.6 g; 3.63 mmol) was
Alkylation of 2',4'-dihydroxy-3'-propylacetophenone produced racemic 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2
-propylphenoxy)pentyloxy]-3,
It was converted to 4-dihydro-2H-1-benzopyran-2-propanoic acid ethyl ester. After purification by chromatography on silica gel (eluting with 9:1 and 4:1 toluene-ethyl acetate), the ester product was obtained as a pale yellow oil in 79% yield (1.6 g). Example 89 Using the method of Example 69, the ester product according to Example 88 (1.6 g; 2.89 mmol) was saponified and
After recrystallization from ethyl acetate-hexane and then acetonitrile, racemic 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy) was obtained as a colorless solid with a melting point of 126.5-129°C. 1 g (66%) of pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-propanoic acid was obtained. Elemental Analysis: _Calculated for _C30H38O8 : C, _68.42 ; H, 7.27 Found: C, 68.42; H, 7.49 Example 90 Using the method of Example 30, the aldehyde product according to Example 83 2.7 g (10 mmol) toluene 30
4-(triphenylphosphoranylidene)-2 in ml
- Condensed with 4.4 g (12 mmol) of ethyl butanoate (3.5 hours at 100° C.). The crude product was chromatographed on 100 g of silica gel, eluting with toluene and 19:1 toluene-ethyl acetate;
Racemic 5-[3,4-dihydro-7] as a yellow oil
-(phenylmethoxy)-2H-1-benzopyran-2-yl]-2,4-pentadienoic acid ethyl ester (mixture of E- and Z-isomers) 1.1 (30
%) was obtained. Example 91 Dienoic acid ester product according to Example 90 (1.1
3.02 mmol) was hydrogenated over 0.95 g of 10% palladium on carbon in 15 ml of ethyl acetate at atmospheric pressure and room temperature. The catalyst was separated and the liquid was concentrated under reduced pressure to give 0.9 g (100%) of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentaic acid ethyl ester as a pale yellow oil.
I got it. Example 92 Using the method of Example 41, the pentanoate ester product according to Example 91 was prepared as racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H- as a yellow oil that crystallized on standing. 1benzopyran-2-pentanoic acid ethyl ester (0.4g; 41%)
It was transformed into. Example 93 Acetyl pentanoate ester according to Example 92 (0.4 g; 1.25 mmol) using the method of Example 65
racemic 6-acetyl-7-[(5-
bromopentyl)oxy]-3,4-dihydro-
Converted to 2H-1-benzopyran-2-pentanoic acid ethyl ester; this oil was subjected to column chromatography on silica gel (eluting with 19:1 toluene-ethyl acetate) in 51% yield (0.3 g).
Obtained with. Example 94 Using the method of Example 67, the bromoester product according to Example 93 (0.3 g; 0.64 mmol) was converted to 2',
Alkylation of 4'-dihydroxy-3'-propylacetophenone produces racemic 6-acetyl-7
-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-
It was converted to dihydro-2H-1-penzopyran-2-pentanoic acid ethyl ester. After purification by chromatography on silica gel (19:1
(eluted with toluene-ethyl acetate), the ester product was obtained as a yellow oil in 80% yield (0.3 g). Example 95 Using the method of Example 69, the ester product according to Example 94 (0.3 g; 0.51 mmol) was saponified and
Melting point 116-120.5℃ after recrystallization from acetonitrile
Racemic 6-acetyl-7- as a colorless solid
0.137 g (48%) of [5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoic acid was obtained. Elemental analysis: Calculated for C ₃₂ H ₄₂ O ₈ : C, 69.29; H, 7.63 Found: C, 69.35; H, 7.66 Example A (racemic)-6-acetyl- as an active ingredient in the composition of capsules 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)
propoxy]-2-methyl-8-propyl-2H-
1-Benzopyran-2-propanoic acid can be used as follows:

[Table] Weight manufacturing method: Mix the active ingredients, lactose and starch in a suitable mixer. Add talc and mix thoroughly. Fill capsules with suitable equipment. Example B (racemic)-7-[3-(4-acetyl-3-) as active ingredient in the composition of tablets (wet granulation)
Hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid can be used as follows:

Table: Preparation: The active ingredient, lactose, modified starch and pregelatinized starch are mixed in a suitable mixer.
Granulate to appropriate hardness with sufficient distilled water. Smash. Dry in a suitable oven. Mill and mix for 3 minutes with magnesium stearate. Compact in a suitable press with suitable punches. Example C (racemic)-6-acetyl-7-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
-1-Benzopyran-2-carboxylic acid can be used as follows: Ingredients mg/tablet Active ingredient 25 Lactose 181 Avicel 55 Starch for direct compression 35 Magnesium stearate 4 Tablet weight 300 mg Manufacturing method : Mix the active ingredient with an equal amount of lactose. Mix thoroughly. Mix with Avicel and direct compression starch and remaining lactose. Mix thoroughly. Add magnesium stearate and mix for 3 minutes. Compact in a suitable press with suitable punches. Example D (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]- as an active ingredient in the composition of an aerosol (Freon suspension aerosol)
3,4-dihydro-2H-1-benzopyran-2
- Carboxylic acids can be used as follows:

[Table] Production method: (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-
1-Benzopyran-2-carboxylic acid is pulverized by air friction into particles in the 1-10 micron range and placed in a suitable container. Add glyceryl trioleate at room temperature. Cool the Freon to -30°C and then add it to the mixture. Immediately after adding the Freon, close the container with an accurate appropriate volumetric lightweight valve and add (racemic)-6-acetyl-7-[5-
Place the container in an ultrasonic generator to disperse the (4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. . Example E (racemic) 6-acetyl-7-[5-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3, as active ingredient in the composition of an aerosol (sodium salt freon suspension aerosol) The sodium salt of 4-dihydro-2H-1-benzopyran-2-carboxylic acid can be used as follows:

[Table] Production method: (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-
The sodium salt of 1-benzopyran-2-carboxylic acid is pulverized by air friction into particles in the 1-10 micron range and placed in a suitable container. Add oleic acid at room temperature. Cool the Freon to -30°C and then add it to the mixture. Immediately after adding the Freon, close the container with an accurate appropriate volumetric lightweight valve and add (racemic)-6-acetyl-7-[5-
in an ultrasonic generator to disperse the sodium salt of (4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydrotoxy-2H-1-benzopyran-2-carboxylic acid. Put the container in. Example F (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]3,4 as active ingredient in the composition of an aerosol (Freon solution aerosol) −
Dihydro-2H-1-benzopyran-2-carboxylic acid can be used as follows: Ingredients

[Table] Production method: (racemic)-6-acetyl-7 in a suitable container
-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-
Dihydro-2H-1-benzopyran-2-carboxylic acid is dissolved in dimethyl sulfoxide at room temperature.
Add ethanol and methylene chloride to this mixture. Next, add Freon cooled to -30°C. Immediately after adding the Freon, close the container with an accurate, suitable volumetric lightweight valve. Example G (racemic)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy] as active ingredient in the composition of an aerosol (Freon solution aerosol)
-3,4-dihydro-2H-1-benzopyran-
The 2-carboxylic acid can be used as follows: Ingredients Active ingredient 50.0mg Dimethyl sulfoxide 150μ Ethanol (99.9%) 0.3ml Methylene chloride 0.5ml Freon 12 4.2ml Total volume 5.0ml Concentration of active ingredient 1mg/0.1 ml Manufacturing method: In this practical example, the same method as in Example F was used. Example H (racemic)-6-acetyl-7-[5-
(4-Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid can be used as follows.

[Table] Phosphate buffer containing sodium hydroxide (in a phosphate buffer containing an equimolar amount of sodium hydroxide) to yield a solution with a pH value of 7.8. racemic)-6-acetyl-7-[5-(4-acetyl-
3-Hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is dissolved.

Claims (1)

[Claims] 1. General formula In the formula, R ¹ is hydrogen or lower alkyl,
R ² is hydrogen or halogen, R ³ , R ⁴ and R ⁵
are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, R ⁶ and R ⁷ are both hydrogen, and R ⁸ is the group −COOR ⁹ ,
or R ⁶ is hydrogen or lower alkyl and R ⁷
is the group -( _CH2 )n- ^COOR9 , and ^R8 is hydrogen and ^R9 is hydrogen or lower alkyl,
X is ( _C3-7 )-alkylene and n is 0
is an integer of ~4, and when ^R9 is hydrogen, its salts with pharmaceutically acceptable bases. 2 R ⁶ is hydrogen or lower alkyl, R ⁷ is the group -(CH ₂ )n-COOR ⁹ , R ⁸ is hydrogen, and R ⁹ and n are as defined in claim 1. A compound according to claim 1, which is as follows. 3 General formula Claims that are a compound of the formula, wherein R ¹¹ is lower alkyl, R ³¹ is acyl, X is (C _3-7 )-alkylene, and n is an integer from 0 to 4. A compound according to item 1. 4 R ¹ is lower alkyl, R ² is hydrogen,
3. A compound according to claim 2, wherein R ³ is acyl and R ⁴ , R ⁵ , R ⁶ and R ⁹ are hydrogen. 5. A compound according to claim 4, wherein X is alkylene having 3 to 5 carbon atoms. 6. The compound according to claim 5, wherein R ³ is acetyl. 7. The compound according to claim 6, wherein R ¹ is propyl. 8 (racemic)-6-acetyl-7-[5-(4-
Acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H
The compound according to claim 1, which is -1-benzopyran-2-carboxylic acid. 9 (racemic)-7-[3-(4-acetyl-3-
The compound according to claim 1, which is hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. 10 (racemic)-6-acetyl-7-[3-(4
2. The compound according to claim 1, which is -acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid. 11 (racemic)-6-[3-(4-acetyl-3
-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1
-benzopyran-2-carboxylic acid. 12 (racemic)-7-[3-(4-acetyl-3
-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-
The compound according to claim 1, which is 1-benzopyran-2-carboxylic acid. 13 (racemic)-6-acetyl-7-[3-(4
-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-
The compound according to claim 1, which is benzopyran-2-carboxylic acid. 14 General formula where R ³ , R ⁴ and R ⁵ are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, and R ⁶¹ and R ⁷¹ are both hydrogen, and
R ⁸¹ is the group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is the group -(CH ₂ ) n-
A compound of COOR ⁹¹ , and R ⁸¹ is hydrogen, R ⁹¹ is lower alkyl, and n is an integer from 0 to 4. 15 General formula where R ³ , R ⁴ and R ⁵ are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, and R ⁶¹ and R ⁷¹ are both hydrogen, and
R ⁸¹ is the group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is the group -(CH ₂ ) n-
COOR ⁹¹ , and R ⁸¹ is hydrogen, R ⁹¹ is lower alkyl, X is (C _3-7 )-alkylene, Z is a halogen atom, and n is 0
A compound of which is an integer of ~4. 16 General formula In the formula, R ¹ is hydrogen or lower alkyl,
R ² is hydrogen or halogen, R ³ , R ⁴ and R ⁵
are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, R ⁶ and R ⁷ are both hydrogen, and R ⁸ is the group −COOR ⁹ ,
or R ⁶ is hydrogen or lower alkyl and R ⁷
is the group -( _CH2 )n- ^COOR9 , and ^R8 is hydrogen and ^R9 is hydrogen or lower alkyl,
X is ( _C3-7 )-alkylene and n is 0
is an integer of ~4, and when R ⁹ is hydrogen, in producing a salt thereof with a pharmaceutically acceptable base, (a) General formula or where R ⁶¹ and R ⁷¹ are both hydrogen and R ⁸¹ is a group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is a group -
( _CH2 )n-COOR ⁹¹ , and ^R81 is hydrogen, ^R91 is lower alkyl, and
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as described above, and each compound has the general formula as well as where R ⁶¹ and R ⁷¹ are both hydrogen and R ⁸¹ is a group -COOR ⁹¹ or R ⁶¹ is hydrogen or lower alkyl and R ⁷¹ is a group -
( _CH2 )n- ^COOR91 , and ^R81 is hydrogen, ^R91 is lower alkyl, X is ( _C3-7 )-alkylene, Z is a halogen atom, and ^R1 , R ² , R ³ , R ⁴ , R ⁵ and n
is as described above, or (b) the general formula In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶¹ , R ⁷¹ and
R ⁸¹ is as described above, the ester group in the compound is hydrolyzed, and if necessary, the resulting racemate is resolved into optically active isomers, and/or the resulting R ⁹ is hydrogen. A compound of the above general formula, characterized in that the compound of the formula is converted into a pharmaceutically acceptable salt with a base, and
When R ⁹ is hydrogen, a method for producing a pharmaceutically acceptable base and its salt. 17 General formula In the formula, R ¹ is hydrogen or lower alkyl,
R ² is hydrogen or halogen, R ³ , R ⁴ and R ⁵
are independently hydrogen, acyl or lower alkyl, provided that only one of R ³ , R ⁴ and R ⁵ can be acyl, R ⁶ and R ⁷ are both hydrogen, and R ⁸ is the group −COOR ⁹ ,
or R ⁶ is hydrogen or lower alkyl and R ⁷
is the group -( _CH2 )n- ^COOR9 , and ^R8 is hydrogen and ^R9 is hydrogen or lower alkyl,
X is ( _C3-7 )-alkylene and n is 0
An anti-allergic agent characterized by containing as an active ingredient a compound of the following, or a salt thereof with a pharmaceutically acceptable base when R ⁹ is hydrogen. 18 (racemic)-6-acetyl-7-[5-(4
-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-
The antiallergic agent according to claim 17, which contains 2H-1 benzopyran-2-carboxylic acid as an active ingredient.